Vitamins and regulation of angiogenesis: [A, B1, B2, B3, B6, B9, B12, C, D, E, K]

Journal of Functional Foods 38 (2017) 180–196

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Journal of Functional Foods journal homepage: www.elsevier.com/locate/jff

Vitamins and regulation of angiogenesis: [A, B1, B2, B3, B6, B9, B12, C, D, E, K] Mohammad Ali Saghiri a,b,⇑, Armen Asatourian c, Soroush Ershadifar c, Mona Momeni Moghadam c, Nader Sheibani a,b,d a

Departments of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States Departments of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States Angiogenesis and Regenerative Sector, Dr. H. Afsar Lajevardi Research Cluster, Shiraz, Iran d Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States b c

a r t i c l e

i n f o

Article history: Received 29 June 2017 Received in revised form 3 September 2017 Accepted 3 September 2017

Keywords: Angiogenesis Caner therapy Regeneration Vitamins Wound healing

a b s t r a c t Angiogenesis is one of the most important processes during wound healing, tissue regeneration, and tumor growth. Vitamins are one of the most important micronutrients, which play great roles in many biochemical reactions inside the cells and cell pathways affecting various cellular functions. Here the effects of essential vitamins on angiogenesis are overviewed. An electronic search was performed in PubMed database via OVID from January 2000 to February 2017 using the keywords regarding the effects of vitamins on angiogenesis. Of the 911 articles found in our initial search only 126 met the inclusion criteria. Vitamin A, both 13-cis retinoid acid and acyclic acid inhibit angiogenesis by suppressing VEGF, while all trans retinoid acid induces angiogenesis by enhancing the expression of proangiogenic factors and reducing pro-MMP2 activity. Vitamin B1, Thiamine, simulates angiogenesis by inducing proliferation of human endothelial progenitor cells and inhibiting apoptosis via PKB/Akt-mediated potentiation. Vitamin B2, Riboflavin, inhibits angiogenesis by decreasing phosphorylation of Src tyrosine 16, an activator residue of Src kinase, and a key player in angiogenesis. Vitamin B3, Niacin, acts as a proangiogenic substance by acting as a precursor of NAD+, as well as promoting endothelial cell function via its receptor GPR109A. Vitamin B6 inhibits angiogenesis by inhibiting micro vessel outgrowth and suppressing the proliferation of endothelial cells. Vitamin B9, Folic acid, inhibits angiogenesis by decreasing proliferation of endothelial cells, as well as activating Src/ERK2/NF-jB/p53 signaling pathways, resulting in cell cycle arrest. Vitamin B12, Cobalamin, acts as a pro-angiogenic substance by inducing production of NO, prostaglandin E1, and prostacyclin leading to angiogenesis. Furthermore, vitamin B12 reduces homocysteine levels in plasma, which is a significant anti-angiogenesis agent. Vitamin C in high concentrations alters the metabolic activity of endothelial cells; decreasing their ATP levels and cell proliferation. Thus, vitamin C has anti-angiogenic properties. Vitamin D in the 1,25D3 form has anti-proliferative effects by inducing cell cycle arrest and apoptosis. Vitamin E, Tocopherols, exhibit anti-angiogenic effects by inhibition of proliferation and tube formation of endothelial cells through suppression of signaling pathways that are dependent on activation of PI3K/PDK/Akt signaling. Vitamin K exhibits its antiangiogenic activity by acting on protein S, through inhibition of vascular endothelial growth factor-receptor 2 (VEGFR2)-dependent vascularization as well as VEGF induced endothelial cell migration and proliferation. According to the studies evaluated here, vitamins A, B, C, D, E and K exhibit pro- or anti-angiogenic activities based on their derivatives and physiological settings. Vitamin A shows both anti- and proangiogenesis activity while Vitamins B2, B6, B9, C, D, E and K have anti-angiogenic properties and Vitamins B1 and B3 are proangiogenesis. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction ⇑ Corresponding author at: Department of Ophthalmology & Visual Sciences, University of Wisconsin School of Medicine and Public health, 1111 Highland Avenue, 9418 WIMR, Madison, WI 53705, United States. E-mail address: [email protected] (M.A. Saghiri). http://dx.doi.org/10.1016/j.jff.2017.09.005 1756-4646/Ó 2017 Elsevier Ltd. All rights reserved.

Consuming sufficient levels of essential nutrients and maintaining their homeostasis is essential for proper body functions (Lichtenstein & Russell, 2005). In general, the essential nutrients

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are classified into 5 categories: (a) water, (b) vitamins, (c) minerals, (d) amino acids (proteins), and (e) fatty acids. Each of these five categories plays an important role in governing body functions, and their absence in diet could lead to organ dysfunction and growth impairment (Lichtenstein & Russell, 2005). The significance of vitamins and their relevancy in today’s diet make study of their effects on various biological mechanisms a priority (Gerald F. Combs, 2017). Based on a survey conducted on US adults, it was discovered that more than half already take some form of multivitamins (Swift, 2013). The significant and variety of functions that vitamins have such as maintaining healthy teeth and skin, forming blood cells, and regulation of metabolism add further emphasis on studying their biological effects (Gerald F. Combs, 2017; Saghiri, Asatourian, Orangi, Sorenson, & Sheibani, 2015b; Trumbo, Yates, Schlicker, & Poos, 2001). Angiogenesis is a biological process by which new blood vessels expand from preexisting capillaries (Ioachim, 2017; Saghiri, Asatourian, Garcia-Godoy, & Sheibani, 2016b), such as a vascular labyrinth of capillaries by means of budding from the primary vessel into a viable capillary bed (Li, Li, Hutnik, & Chiou, 2012; Saghiri, Asatourian, Garcia-Godoy, & Sheibani, 2016a). All these processes occur in response to different factors and signals (Hoeben et al., 2004; Maltby, Khazaie, & McNagny, 2009; Martin et al., 2014; Saghiri, Asatourian, Garcia-Godoy, & Sheibani, 2016d) including vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF2), heparin, and transforming growth factor-a (TNFa) (Maltby et al., 2009), which induce migration, growth and differentiation of endothelial cells (Li et al., 2012; Saghiri, Asatourian, Garcia-Godoy, & Sheibani, 2016c). Under non-pathologic conditions, angiogenesis plays a vital role in placentation and embryonic development during pregnancy (Li et al., 2012), wound healing (Gargett & Rogers, 2001; Saghiri, Asatourian, & Sheibani, 2015), and menstrual cycle (Nussenbaum & Herman, 2010; Ramezani et al., 2017). However, angiogenesis destructive effect can be seen in pathologic conditions such as malignancies and tumor metastasis (Gargett & Rogers, 2001; Saghiri, Orangi, Asatourian, Sorenson, & Sheibani, 2016), chronic inflammatory disease including arthritis, atherosclerosis (Carmeliet, 2003), diabetes and asthma. After first description of angiogenesis concept in tumor by Folkman (2002), Mamede et al. (2011), many studies have shown a strong relationship between solid tumor establishment, growth, metastasis and angiogenesis (Folkman, 2002; Saghiri, Asatourian, Orangi, Sorenson, & Sheibani, 2015a). Angiogenesis is a key step in tumor growth and metastasis, initiated by altered productions of proangiogenic and antiangiogenic factors leading to the ‘‘angiogenic switch”. (Folkman, 2002; Saghiri et al., 2016b). In order for tumors to grow and form metastasis, they should undergo the ‘‘angiogenic switch”, which is a state caused by disturbances in production of pro- and anti-angiogenic factors (Folkman, 2002). This results in development of new blood vessels to provide oxygen and nutrients for the growing tumor (Nussenbaum & Herman, 2010; Saghiri, Orangi, et al., 2016). Vitamins are one of the most important micronutrients with critical roles during several biological processes including angiogenesis. The aim of this review was to evaluate the angiogenic effects of vitamins A, B, C, D, E, and K, and to determine their potential use as either pro- or anti-angiogenic agents.

2. Materials and methods 2.1. The review purpose Present review was performed to evaluate angiogenic properties of vitamins A, B, C, D, E, and K. The pro- and/or antiangiogenic effects of these vitamins are discussed.

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2.2. Inclusion and exclusion criteria The inclusion criteria were: (a) studies accepted and published from January 2000 to February 2017; (b) the scientific in-vitro or in-vivo studies, reviews, systematic reviews, case reports with controlled study design; and (c) studies that presented mechanisms by which vitamins affected angiogenesis. The exclusion criteria were: (a) studies that were published before January 2000 or after February 2017; (b) Studies that investigated the effects of vitamins on cancer cells without addressing the mechanism; and (c) studies that used vitamins as a substance to enhance and/or demonstrate the effects of another substance. 2.3. Search methodology The electronic searches were performed in the PubMed database via OVID using keywords mentioned in the PubMed and MeSH headings, including angiogenic effects of vitamins. 2.4. Search strategy In the electronic search of scientific papers in the PubMed database the following keywords were used: ‘‘vitamin A in angiogenesis”, ‘‘Thiamine in angiogenesis”, ‘‘Riboflavin in angiogenesis”, ‘‘Niacin in angiogenesis”, ‘‘vitamin B6 in angiogenesis”, ‘‘biotin in angiogenesis”, ‘‘Folic acid in angiogenesis”, ‘‘vitamin C in angiogenesis”, ‘‘vitamin D in angiogenesis”, ‘‘vitamin E in angiogenesis”, ‘‘vitamin in angiogenesis development NOT cancer”, ‘‘vitamin K in angiogenesis”, and ‘‘vitamin B12 in angiogenesis”. It should be noted that the search results using the keywords ”thiamine‘‘ and ”vitamin B1”, ‘‘Riboflavin” and ‘‘vitamin B2”, ‘‘Niacin” and ‘‘vitamin B3”, ‘‘Biotin” and ‘‘vitamin B7, and ‘‘folic acid” and ‘‘vitamin B9” were similar, while the search using the keywords ‘‘vitamin A”, ”vitamin C”, ‘‘vitamin D ”, ‘‘vitamin E”, and ”vitamin K” showed more results rather than using the generic name for the vitamins. The relevant full text articles and their reference lists were evaluated to supplement the search. Two reviewers independently performed the assessment of the eligibility and related data. 3. Results The initial search of the keywords indicated above resulted in 911 articles, and only 126 met the inclusion criteria set for this review. The selected studies were related to the angiogenic properties of vitamins. 4. Discussion In this part, we aimed to discuss the pro- and/or anti-angiogenic activity of vitamins A, B, C, D, E, and K. 4.1. Vitamin A One of the four fat-soluble vitamins, vitamin A or retinol belongs to a group called retinoids (Fletcher & Fairfield, 2002). There are different forms of vitamin A such as retinol, retinoid acid and a- and b-carotene (Allen, Britton, & Leonardi-Bee, 2009; Damodaran, Parkin, & Fennema, 2008). Main sources of retinol are dairy, especially butter and animal products such as fish and egg yolk. Daily uptake of pro-vitamin A and pre-vitamin A in a form of retinol and b-carotene is essential for proper eyesight, intact healthy skin and mucus, normal growth, and immune system. The synthetic form of this organic compound has been exploited in treatment of some diseases. At the molecular level, retinol plays a role in cell differentiation and apoptosis (Doldo et al., 2015;

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Fletcher & Fairfield, 2002). Our initial search for ‘‘vitamin A in angiogenesis” resulted in 108 articles, of which nine met our criteria and are discussed here. 4.1.1. Anti-angiogenic effects Based on a study by Hoffmann et al. (2007), 0.1/10 mM 13-cis retinoid acid lowered proliferation in thyroid cancer up to 26– 34% in two weeks by reducing VEGF levels in vitro. In vivo, tumor shrunk in animals receiving retinoic acid (RA), ranging from 6% to 33%. Thus, concluding that suppressing angiogenesis could be a basic mechanism responsible for therapeutic effect of RA, and also its direct anti-proliferative effect on endothelial cells (Hoffmann et al., 2007). Furthermore, Yusuke Komi and coworkers (Komi et al., 2009) revealed that ACR (acyclic retinoid) inhibits angiogenesis in the chicken chorioallantoic membrane assay. The exact effect of ACR is through inhibition of phosphorylation of both VEGF receptor 2 (VEGFR2) and extracellular signal regulated kinase (ERK). Through these mechanisms the suppression of VEGFR2/ MAPK pathway subsequently occurs (Komi et al., 2009). Additionally, other studies have shown that RA selectively inhibits vascular permeability by affecting VEGF production. VEGF causes changes in permeability of endothelial cells, migration and division, suggesting that the suppressive effect of RA on angiogenesis and vessel permeability is not related to FGF2 and histamine, but indeed, it is related to RA selective inhibition of the angiogenic response induced by phosphorylation of PLC-c and synthesis of cGMP. Thus, the major function of RA is to improve angiogenesis and permeability through modulation of VEGF levels (Pal et al., 2000). Another study published in 2010 showed bexarotene, a type of retinoid that activates retinoid X receptor or RXR, acts as an anticancer compound through attenuation cell cycle and angiogenesis (Qu & Tang, 2010). The effect of all trans retinoic acid (ATRA) on the growth of myeloma xenografts in nude mice, along with the influence of rosiglitazone (RGZ) and ATRA on VEGF expression and angiogenesis in the tumor, was evaluated by Huang et al. (2012). The myeloma xenograft mice received ATRA or ATRA+RGZ by subcutaneous injection every day for 21 days, and the control mice received same amount of saline per day. The lowest weight of xenograft and least angiogenesis was found in RGZ+ATRA group. They concluded that inhibition of VEGF expression, along with induction of apoptosis and differentiation resulted in prevention of angiogenesis by RGZ+ATRA (Huang et al., 2012). 4.1.2. Pro-angiogenic effects A study performed by Pierce et al. (2007) evaluated the effect of retinoid in lung elastin formation and angiogenesis in premature ventilated baboons subjected to surfactant treatment and placed on positive pressure and supplemental oxygen. ‘‘Five animals received daily retinol supplementation (5 mg/kg; Aquasol A was delivered by intramuscular injection) and five received vehicle injections alone.” They concluded that retinoic acid does not affect the microvasculature of terminal air space or improve VEGF expression compared with control group. In contrast, an in vivo study (Pierce et al., 2007) suggested the proliferation of endothelial cell and stimulation of VEGF factor as well as formation of new blood vessels. Pourjafar, Saidijam, Mansouri, Ghasemibasir, and Najafi (2017) evaluated the impact of ATRA on the survival, migration, and pro-angiogenesis properties of mesenchymal stem cell in vitro, as well as using a wound healing model in vivo. Incubation of mesenchymal stem cells with ATRA resulted in increased expression of chemokine receptors and angiogenic factors including COX-2, HIF-1, CXCR4, CCR, VEGF, Ang-2 and Ang-4, and had a positive impact on wound healing in vivo. In addition, incubation of endothelial cells with ATRA resulted in enhanced sprouting (Pourjafar et al., 2017). In contrast, incubation of human breast

cancer cells (MCF-7) cells with ATRA reduced pro-matrix metalloproteinase-2 (pro-MMP2) activity, and consequently angiogenesis, through decreased production of VEGF (Dutta, Sen, Banerji, Das, & Chatterjee, 2009). MMPs are essential in the process of matrix degradation and cell-to-cell and/or matrix attachment for malignant behavior of tumor cells such as invasion and angiogenesis along with growth. Further studies examining the effect of ATRA on angiogenesis, in the form of capillary-like tube formation using human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts (NHDF), showed enhanced capillary formation along with increased HUVEC proliferation. ATRA and Am80 induced VEGF secretion by NHDF, and induced VEGFR2 mRNA expression in HUVEC. ATRA also induced secretion of hepatocyte growth factor as well as angiopoietin-2 in the co-culture. All these including the possibility of stimulating HUVEC proliferation and enhanced VEGF signaling, as well as hepatocyte growth factor and angiopoitin-2 production, suggested that ATRA enhances angiogenesis (Saito et al., 2007) (Fig. 1A). 4.2. Vitamin B1 Classified as an essential water-soluble vitamin, dietary intake of vitamin B1 (Thiamin) is required to maintain carbohydrate metabolism (Institute of Medicine (US), 1998). Presence of thiamine is necessary in the activity of four key enzymes in cellular metabolism (Zastre, Sweet, Hanberry, & Ye, 2013): pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (a-KGDH) in the tricarboxylic acid (TCA) cycle, transketolase (TKT) within the pentose phosphate pathway (PPP), and branched chain alpha-keto acid dehydrogenase complex (BCKDC) involved in amino acid catabolism (Institute of Medicine (US), 1998; Loew, 1996). Thiamine mainly exists in interconvertible phosphorylated forms, most commonly as Thiamin pyrophosphate (TPP), which is responsible for the actions mentioned above (Institute of Medicine (US), 1998). Thiamine is naturally found in many food sources such as bread, fish, and meat. It is also used for fortification in processed foods (Gangolf et al., 2010; Institute of Medicine (US), 1998; Loew, 1996). In addition, most over-the-counter vitamin supplements contain a significant amount of thiamin, ranging from 100 to 6600% of the recommended daily intake (Institute of Medicine (US), 1998). Our initial search of ‘‘thiamine in angiogenesis” identified 7 studies, of which six qualified for this review. One of the most published derivatives of thiamine is Benfotiamine (Loew, 1996). This lipophilic substance (Patel, Patel, & Prajapati, 2012) mediates the shunting of triose glycolytic intermediates toward reductive pentose pathway (Babaei-Jadidi, Karachalias, Ahmed, Battah, & Thornalley, 2003). Benfotiamine increased transketolase expression (Babaei-Jadidi et al., 2003), and reduced aldose reductase mRNA expression and intracellular glucose and sorbitol levels (Berrone, Beltramo, Solimine, Ape, & Porta, 2006) in human endothelial cells and bovine retinal pericytes cultured in high glucose. In vitro, benfotiamine stimulated the proliferation of human endothelial precursor cells (EPC), while inhibiting apoptosis induced by high glucose (Atta-ur-Rahman, 2014; Berrone et al., 2006). Collectively, these studies suggest that benfotiamine aids the post-ischemic healing of diabetic animals via PKB/Akt-mediated potentiation of angiogenesis and inhibition of apoptosis. In addition, experiments in diabetic mice whose number of circulating EPC was reduced showed that this deficit can be corrected by benfotiamaine (Berrone et al., 2006). Furthermore, benfotiamine prevented the vascular accumulation of advanced glycation end products and the induction of pro-apoptotic caspase-3, while restoring proper expression of NOS3 and Akt in the ischemic muscles (Atta-ur-Rahman, 2014; Gadau et al., 2006). These benefits of benfotiamine were nullified by expression

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Fig. 1. Schematic figure of role of vitamins in angiogenesis process. (A) Role of vitamin A in angiogenesis; (B) role of vitamin B1 in angiogenesis; (C) role of vitamin B2 in angiogenesis.

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of a dominant-negative PKB/Akt (Gadau et al., 2006) (Fig. 1B) (Table 1). 4.3. Vitamin B2 Vitamin B2 (Riboflavin) is a water-soluble, yellow florescent compound. Main form of riboflavin is an essential part of coenzymes flavin mononucleotide (FMN) and flavin-adenine dinucleotide (FAD) (McCormick, 1972; Merrill & McCormick, 1980). In these bound coenzyme forms, riboflavin functions as a catalyst for redox reactions in numerous metabolic pathways and production of energy (McCormick, 1989). FAD plays a crucial role in electron transport chain, an essential part of energy production (Powers, 1999). Furthermore, flavocoenzymes participate in redox reactions such as: flavoprotein-catalyzed dehydrogenations, reactions with sulfur-containing compounds, hydroxylations, oxidative decarboxylations, dioxygenations, and reduction of oxygen to hydrogen peroxide (McCormick, 1972). Plant and animal tissues contain small amounts of riboflavin; milk is a rich and accessible source of riboflavin that is commonly consumed (Institute of Medicine (US), 1998). Riboflavin deficiency is common with other nutrient deficiencies (McCormick, 1989). The search for ‘‘riboflavin in angiogenesis” identified 5 results, two of which met the criteria for this review. In a preset study conducted on breast cancer patients, a daily supplement of CoQ, riboflavin and niacin, one dosage per day, along with tamoxifen (TAM) twice per day was given to 84 randomly selected patients (Premkumar, Yuvaraj, Sathish, Shanthi, & Sachdanandam, 2008). The serum levels of proangiogenic factors were elevated in untreated breast cancer patients. However, their levels were found to be reduced in patients undergoing TAM therapy for more than 1 year (Premkumar et al., 2008). Studies on iRF (photoproducts of riboflavin) have shown decreased phosphorylation of Src tyrosine 16, an activator residue of Src kinase (Sen & Johnson, 2011). This non-receptor protein tyrosine kinase is considered to be a key player in tumor progression, providing oncogenic signals for cell survival, metastasis and angiogenesis (Sen & Johnson, 2011). This study concluded the anti-angiogenic effects of iRF in tumor cells (Fig. 1C) (Table 1). 4.4. Vitamin B3 Vitamin B3, Niacin, is generally referred to as nicotinamide (nicotinic acid amide), nicotinic acid (pyridine-3-carboxylic acid), and any derivatives exhibiting the biological activity of nicotinamide (Institute of Medicine (US), 1998). Niacin functions in various biological redox reactions in forms of coenzymes NAD and NADP (Institute of Medicine (US), 1998). NAD plays a role in intracellular respiration and as co-dehydrogenase with enzymes involved in oxidation of fuel molecules such as glyceraldehyde 3-phosphate, lactate, alcohol, 3-hydroxybutyrate, pyruvate, and a-ketoglutarate. Additionally, NADP functions in reductive biosynthesis like fatty acid and steroid synthesis, and similar to NAD, as a codehydrogenase (Institute of Medicine (US), 1998). Niacin could be found in mature cereal grains but because of its bound form, only 30 percent is available, and with alkali treatment of the grains the percentage absorbed increases (Carpenter & Lewin, 1985). Niacin, in coenzyme NAD/NADP forms in meats, appears to be much more available (Institute of Medicine (US), 1998). Most common symptoms of niacin deficiency involve skin and digestive/ nervous system diseases and syndromes (Shils & Shike, 2006). Our search for ‘‘niacin in angiogenesis” resulted in 14 articles, 3 of which met our criteria. Niacin acts as a potential biosynthetic precursor for NAD (+), and elicits vascular benefits through NAD (+)-dependent sirtuin (SIRT) mediated responses. Additionally, niacin acts through its receptor, GPR109A, to promote proangiogenic

function of endothelial cell. Its angiogenic function in excess palmitate was assessed by tube formation following treatment of human microvascular endothelial cells (HMVEC) with either a relatively low concentration of niacin (10 lM) or nicotinamide mononucleotide (NMN) (1 lM), a direct precursor for NAD (+) (Hughes-Large et al., 2014). Further observations revealed HMVEC express GRP109A. Activation of this receptor with either Acrfran or MK-1903 recapitulated niacin-induced improvements in HMVEC tube formation, while GPR109A siRNA diminished the effects of niacin. These studies suggested that while niacin, at low concentration, improves HMVEC angiogenic function under lipotoxic conditions, it is very likely that Niacin acts independently of NAD (+) biosynthesis and SIRT1 activation through niacin receptor activation (Chen et al., 2007; Hughes-Large et al., 2014). Research on Niaspan has shown that it increases the expression of VEGF and angiopoietin-1 (Ang1) and phosphorylation of Akt, NOS3, and Tie2 in the ischemic brain. Niacin upregulated Ang1 expression in cultured brain endothelial cells and increased vascular endothelial growth factor, Ang1, and NOS3 expression in cultured astrocytes, and dose-dependently increased capillary tube formation compared with non-treatment control (Chen et al., 2007; Pang, Hughes-Large, Robson, Chan, & Borradaile, 2014). Inhibition of NOS partially decreased niacin-induced capillary tube formation. Inhibition of phosphoinositide 3-kinase or knockdown of Tie2 significantly decreased niacin-induced capillary tube formation (Pang et al., 2014). Niacin increases HDL and promotes angiogenesis, which may contribute to improvement of functional outcome after stroke. The Ang1/Tie2, phosphoinositide 3-kinase/Akt, and NOS3 pathways appear to mediate niacin-induced angiogenesis (Chen et al., 2007). Niacin improves HMVEC angiogenic function under lipotoxic and hypoxic conditions. During normoxia, this effect appears to be independent of NAD+ synthesis and SIRT1 activation, but likely occurs through activation of GPR109A (Pang et al., 2014) (Fig. 2A) (Table 1). 4.5. Vitamin B6 Vitamin B6 acts as a coenzyme in metabolism of amino acids, glycogen, and sphingoid bases. Vitamin B6 contains a group of six similar substances: pyridoxal (PL), pyridoxine (PN), pyridoxamine (PM), and their respective 50 -phosphates (PLP, PNP, and PMP). PLP, as a coenzyme for more than 100 reactions involving amino acid metabolism, includes aminotransferases, decarboxylases, racemases, and dehydratases. It is a coenzyme for daminolevulinate synthase, a critical part in heme biosynthesis. Most of PLP in the body is contained in muscle bound to phosphorylase. The classical symptoms for B6 deficiency include seborrheic dermatitis (Vilter et al., 1950), microcytic anemia (Snyderman et al., 1953), epileptiform convulsions (Bessey, Adam, & Hansen, 1957; Coursin, 1954) and depression and confusion (Hawkins & Barsky, 1948). Highly fortified cereals, beef liver and other organ meats, and highly fortified soy-based meat substitutes are rich sources of Vitamin B6. The search for ‘‘vitamin B6 in angiogenesis” resulted in 12 articles, two of which met the criteria for our search. Studies have shown that high concentrations of PLP and pyridoxine cause a complete inhibition of microvessel growth (Matsubara, Mori, Matsuura, & Kato, 2001). Studies on PLP individually has shown that it inhibits microvessel outgrowth almost completely in concentrations of 500 mmol/L and showed antiangiogenic effects in a dose dependent manner (Matsubara et al., 2001). Further investigations showed that PLP and Pl suppress the proliferation of HUVEC (Matsubara, Matsumoto, Mizushina, Lee, & Kato, 2003). These studies suggested that vitamin B6 suppresses endothelial

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Table 1 Table of studies included in present review. Study

Main aspect

Conclusion

Hoffmann et al. (2007)

Suppressing angiogenesis via endothelial cells and VEGF Suppressing angiogenesis by VEGF receptors

Direct anti-proliferative effects of 13-cis retinoid acid on endothelial cells, decreasing VEGF, and reduction of VSD Inhibition of phosphorylation of both VEGF-R2 and extracellular signal regulated kinase by acyclic acid, subsequently suppressing VEGF-R2 MAPK pathway Selectively inhibiting vascular permeability by affecting VEGF by retinoic acid

Komi et al. (2009) Pal et al. (2000) Qu and Tang (2010) Huang et al. (2012) Pourjafar et al. (2017)

Dutta et al. (2009) Saito et al. (2007) Berrone et al. (2006) Atta-ur-Rahman (2014)

Suppressing angiogenesis by effecting on cell permeability Suppressing angiogenesis by acting on cell cycle Suppressing angiogenesis by affecting on cell activities Inducing angiogenesis by expressing proangiogenic factors Inducing angiogenesis by under-expression of VEGF Inducing Angiogenesis by stimulating proliferation Inducing angiogenesis via simulating proliferation in cells Inducing angiogenesis by preventing accumulation of end products

Gadau et al. (2006)

Inducing angiogenesis by PKB/Akt pathways

Premkumar et al. (2008)

Inhibit angiogenesis by decreasing proangiogenic factors Inhibit angiogenesis by decreasing phosphorylation Inducing angiogenesis through different receptors

Sen and Johnson (2011) Hughes-Large et al. (2014)

Chen et al. (2007) Pang et al. (2014) Matsubara et al. (2001) Matsubara et al. (2003) Lin et al. (2012) Guariento et al. (2014) Huo et al. (2015) Lai et al. (2014)

Inducing angiogenesis through expressing growth factors Inducing angiogenic by improving HMVEC function Suppressing angiogenesis by inhibiting vessel growth Suppressing angiogenesis by acting on cell functions Suppressing angiogenesis by acting on the cell cycle Suppressing angiogenesis by changing gene expression Suppressing angiogenesis by acting on cell functions Suppressing angiogenesis by promoting IP-10

Novakovic et al. (2006)

Suppressing angiogenesis by expressing various genes within cells

Das (2015)

Inducing angiogenesis by acting on various mechanisms

Mikirova et al. (2008)

Suppresses angiogenesis by preventing cell proliferation and cell migration

Conejo-Garcia et al. (2004)

Suppressing angiogenesis through altering the production of NO

Du et al. (2012)

Suppressing angiogenesis by regulating the activity of enzymes responsible for HIF Suppressing angiogenesis by altering the activity of angiogenesis related genes Suppressing angiogenesis via affecting endothelial cell functions Suppressing angiogenesis by blocking critical cell functions

Yeom et al. (2009) Chakraborti (2011) Kalkunte et al. (2005)

Ali and Vaidya (2007)

Suppressing angiogenesis by regulating genes

Vitamin D and Cancer. (Springer-Verlag New York, 2011)

Suppressing angiogenesis by increasing the number of receptors and anti-angiogenic subtances

As a selective RXR agonist, Bexarotene effects cell cycle progression, including apoptosis and differentiation, inhibiting angiogenesis Combination of RGZ and ATRA inhibits angiogenesis by inducing apoptosis and differentiation, as well as decreasing VEGF expression Increase in the expression of pro-angiogenic factors, COX-2, HIF-1, CXCR4, CCR, VEGF, Ang-2 and Ang-4, by ATRA leading to angiogenesis, tube formation, and wound healing ATRA acts as a proangiogenic substance by under-expressing VEGF in MCF-7, reducing pro-MMP-2 activity and consequently angiogenesis ATRA induces angiogenesis by Stimulating HUVEC proliferation and enhancement of VEGF signaling as well as hepatocyte growth factor and angiopoitin-2 Benfotiamine simulates angiogenesis via proliferation of human EPC while inhibiting apoptosis induced by high glucose Benfotiamine simulates angiogenesis by preventing vascular accumulation of glycation end products, while inducing pro-apoptotic caspase-3 and restoring NOS3 and Akt expression Benfotiamine induces angiogenesis through inhibition of apoptosis and PKB/Aktmediated potentiation of angiogenesis Serum containing Riboflavin, niacin, and CoQ decrease pro-angiogenesis marker levels and increase anti-angiogenesis factors iRF decreases phosphorylation of Src tyrosine 16, which is an activator of Src Kinase, a key player in cell survival and angiogenesis As a potential biosynthesis precursor for NAD+, Niacin elicits vascular benefits through NAS+ dependent, SIRT responses, as well as promoting endothelial functions through its receptor GPR109A By increasing the expression of VEGF and Ang1, phosphorylation of Akt, NOS3, and Tie2, Niaspan induces angiogenesis Niacin improves HMVEC angiogenic function under lipotoxic and hypoxic conditions through activation of GPR109A High concentrations of PLP and pyridoxine completely inhibit micro-vessel growth, thus inhibiting angiogenesis Vitamin B6 inhibits angiogenesis by suppressing endothelial cell proliferation and inhibiting DNA polymerase and DNA topoisomerases FA up-regulates the expression of p21 and p27, resulting in G0/G1 cell cycle arrest and inhibition of angiogenesis By inhibiting the development of GSTP, treatments with FA change the gene expression in rat liver cells, which are involved in p53 signaling and angiogenesis FA inhibits proliferation by elevating the levels of p21 and p27 proteins and reduces cell migration via inhibiting RhoA activity FA-CS-NPs entrapped IP-10 plasmid promotes IP-10 expression and induces apoptosis in mice tumor, as well as inhibiting angiogenesis Folate deficiency affects the expression of genes related to cell cycle, apoptosis, and finally angiogenesis due to significant difference in folate concentration among the four cell lines By interacting with different mechanisms such as L-arginine-nitric oxide (NO) system, different products like NO, prostaglandin E1, prostacyclin are generated that suppress synthesis of pro-inflammatory cytokines resulting in angiogenesis High concentrations of AA acts as a anti-angiogenic substance by altering the metabolic activity of endothelial cells, decreasing their ATP level without altering their cell viability High concentration if AA inhibits angiogenesis through altering the oxidativereduction status inside the cells, resulting in a decrease in NO availability, limiting angiogenesis and formation of new blood vessels Ascorbate is essential in maintaining the activity of a class of enzymes, which are directly responsible for regulating HIF High doses of AA suppress angiogenesis by preventing the induction of angiogenesis via inhibiting the expression of genes bFGF, VEGF, and MMP-2 1,25D3 acts as an anti-angiogenesis substance through inducing cell cycle arrest and apoptosis of endothelial cells DBP-maf inhibits angiogenesis via blocking critical steps, including: HEC proliferation, migration, tube formation and micro-vessel sprouting; it also exerts its effects via inhibiting VEGF-R2 and ERK1/2 signaling cascades When bound to VDR, calcitriol inhibits angiogenesis by regulating more than 60 genes that exert pro-differentiating, anti-proliferative and anti-metastatic effects on cells, including effects on cell cycle Calcitriol inhibits angiogenesis via increasing the number of VDR and level of apoptogenic protein p27 (Kip 1) in TDEC (continued on next page)

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Table 1 (continued) Study

Main aspect

Conclusion

Kisker et al. (2003)

Savitskaya and Onischenko (2016)

Suppressing angiogenesis by blocking cell proliferation Suppressing angiogenesis by acting on endothelial cell function Suppressing angiogenesis by affecting intracellular functions

Miyazawa, Tsuzuki, et al. (2004)

Suppressing angiogenesis via acting on signaling pathways

Rohlena et al. (2011)

Suppressing angiogenesis by acting on cell cycle

Miyazawa et al. (2008)

Suppressing angiogenesis via actin on cell function

Fraineau et al. (2012)

Suppressing angiogenesis by blocking cellular receptors

Sandur et al. (2010)

Suppressing angiogenesis via regulating gene expression Suppressing angiogenesis via blocking cellular receptors Suppressing angiogenesis via lowering cell receptor and proteins Suppressing angiogenesis via blocking cell receptors as well as cell enzymes

DBP-maf inhibits angiogenesis by blocking HEC proliferation via inhibiting DNA synthesis, significantly inducing S- and G0/G1-phase arrest in HEC T3 inhibits angiogenesis by blocking both proliferation and tube formation of endothelial cell, while also inhibiting new blood vessel formation VES inhibits angiogenesis by affecting intracellular functions such as inducing apoptosis, inhibiting proliferation, and inducing differentiation, resulting in inhibition of angiogenesis T3 inhibits angiogenesis by suppressing the signaling of growth factor-dependent activation of PI3K/PDK/Akt in neoplastic mammary cells, as a result, phosphorylation of various intracellular substances associated with cell proliferation and apoptosis occur Mitochondrially targeted analog of a-tocopheryl succinate (MitoVES) inhibits angiogenesis by inducing apoptosis MitoVES inhibits angiogenesis via killing proliferating endothelial cells, inducing accumulation of reactive oxygen species, and induction of apoptosis in proliferating cells Protein S inhibits angiogenesis by blocking VEGF-R2-dependent vascularization and decreasing the capacity of endothelial cells to form capillary-like networks as well as inhibiting VEGF-A-induced endothelial cell migration and proliferation Vitamin K blocks STAT3, which is pro-angiogenesis via regulating the expression of various gene products significant in cell survival, proliferation, and angiogenesis PS inhibits angiogenesis via blocking VEGF-A-induced endothelial cell VEGF-R2 phosphorylation and activation of mitogen-activated protein kinase-Erk1/2 and Akt VK2 inhibits angiogenesis via lowering levels of Akt and NF-jB present in cells, directly affecting cell migration and angiogenesis Vitamin K3 inhibits angiogenesis via decreasing the expression of luciferase under the control of hypoxia-responsive elements in hypoxic cell, as well as blocking the interaction between the full-length HIF-1a and p300 High concentration if AA inhibits angiogenesis through altering the oxidativereduction status inside the cells, resulting in a decrease in NO availability, limiting angiogenesis and formation of new blood vessels Ascorbate is essential in maintaining the activity of a class of enzymes, which are directly responsible for regulating HIF High doses of AA suppress angiogenesis by preventing the induction of angiogenesis via inhibiting the expression of genes bFGF, VEGF, and MMP-2 1,25D3 acts as an anti-angiogenesis substance through inducing cell cycle arrest and apoptosis of endothelial cells DBP-maf inhibits angiogenesis via blocking critical steps, including: HEC proliferation, migration, tube formation and micro-vessel sprouting; it also exerts its effects via inhibiting VEGF-R2 and ERK1/2 signaling cascades When bound to VDR, calcitriol inhibits angiogenesis by regulating more than 60 genes that exert pro-differentiating, anti-proliferative and anti-metastatic effects on cells, including effects on cell cycle Calcitriol inhibits angiogenesis via increasing the number of VDR and level of apoptogenic protein p27 (Kip 1) in TDEC

De Silva et al. (2016)

Na et al. (2013) Aggarwal et al. (2006) Aggarwal et al. (2009)

Conejo-Garcia et al. (2004)

Suppressing angiogenesis through altering the production of NO

Du et al. (2012)

Suppressing angiogenesis by regulating the activity of enzymes responsible for HIF Suppressing angiogenesis by altering the activity of angiogenesis related genes Suppressing angiogenesis via affecting endothelial cell functions Suppressing angiogenesis by blocking critical cell functions

Yeom et al. (2009) Chakraborti (2011) Kalkunte et al. (2005)

Ali and Vaidya (2007)

Suppressing angiogenesis by regulating genes

Vitamin D and Cancer. (Springer-Verlag New York, 2011) Kisker et al. (2003)

Savitskaya and Onischenko (2016)

Suppressing angiogenesis by increasing the number of receptors and anti-angiogenic substances Suppressing angiogenesis by blocking cell proliferation Suppressing angiogenesis by acting on endothelial cell function Suppressing angiogenesis by affecting intracellular functions

Miyazawa, Tsuzuki, et al. (2004)

Suppressing angiogenesis via acting on signaling pathways

Rohlena et al. (2011)

Suppressing angiogenesis by acting on cell cycle

Miyazawa et al. (2008)

Suppressing angiogenesis via actin on cell function

Fraineau et al. (2012)

Suppressing angiogenesis by blocking cellular receptors

Sandur et al. (2010)

Suppressing angiogenesis via regulating gene expression Suppressing angiogenesis via blocking cellular receptors Suppressing angiogenesis via lowering cell receptor and proteins Suppressing angiogenesis via blocking cell receptors as well as cell enzymes

De Silva et al. (2016)

Na et al. (2013) Aggarwal et al. (2006) Aggarwal et al. (2009)

DBP-maf inhibits angiogenesis by blocking HEC proliferation via inhibiting DNA synthesis, significantly inducing S- and G0/G1-phase arrest in HEC T3 inhibits angiogenesis by blocking both proliferation and tube formation of endothelial cell, while also inhibiting new blood vessel formation VES inhibits angiogenesis by affecting intracellular functions such as inducing apoptosis, inhibiting proliferation, and inducing differentiation, resulting in inhibition of angiogenesis T3 inhibits angiogenesis by suppressing the signaling of growth factor-dependent activation of PI3K/PDK/Akt in neoplastic mammary cells, as a result, phosphorylation of various intracellular substances associated with cell proliferation and apoptosis occur Mitochondrially targeted analog of a-tocopheryl succinate (MitoVES) inhibits angiogenesis by inducing apoptosis MitoVES inhibits angiogenesis via killing proliferating endothelial cells, inducing accumulation of reactive oxygen species, and induction of apoptosis in proliferating cells Protein S inhibits angiogenesis by blocking VEGF-R2-dependent vascularization and decreasing the capacity of endothelial cells to form capillary-like networks as well as inhibiting VEGF-A-induced endothelial cell migration and proliferation Vitamin K blocks STAT3, which is pro-angiogenesis via regulating the expression of various gene products significant in cell survival, proliferation, and angiogenesis PS inhibits angiogenesis via blocking VEGF-A-induced endothelial cell VEGF-R2 phosphorylation and activation of mitogen-activated protein kinase-Erk1/2 and Akt VK2 inhibits angiogenesis via lowering levels of Akt and NF-jB present in cells, directly affecting cell migration and angiogenesis Vitamin K3 inhibits angiogenesis via decreasing the expression of luciferase under the control of hypoxia-responsive elements in hypoxic cell, as well as blocking the interaction between the full-length HIF-1a and p300

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Fig. 2. Schematic figure of role of vitamins in angiogenesis process. (A) Role of vitamin B3 in angiogenesis; (B) role of vitamin B6 in angiogenesis; (C) role of vitamin B9 in angiogenesis.

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cell proliferation and angiogenesis by inhibiting DNA polymerase and DNA topoisomerases (Matsubara et al., 2001; Matsubara et al., 2003) (Fig. 2B) (Table 1).

entrapped Protein-10 plasmids displayed anti-tumor activity by inhibiting angiogenesis and promoted IP-10 expression while inducing apoptosis in tumor cells (Lai et al., 2014; Novakovic et al., 2006) (Fig. 2C) (Table 1).

4.6. Vitamin B7 4.8. Vitamin B12 Search for ‘‘biotin in angiogenesis” resulted in 220 results. Unfortunately, none of them met the requirements for our article; they were mostly concentrated in pinpointing/spotting tumor cells rather than its effects on angiogenesis. 4.7. Vitamin B9 Folate, a common term for this water-soluble B-complex vitamin, functions in single-carbon transfer reactions. Folic Acid (pteroylmonoglutamic acid) is the most oxidized and stable form of folate (Wagner, 1996). Folic acid is rarely present in food, but it is found in a variety of vitamin supplements, and in fortified food products. Folic acid is composed of a p-aminobenzoic acid molecule attached at an end to a pteridine ring and the other to one glutamic acid molecule (Institute of Medicine (US), 1998). Food folates, the most naturally occurring folates, are pteroylpolyglutamates, containing one to six additional glutamate molecules joined in a peptide linkage to the c-carboxyl of glutamate. Coenzymes of folate are involved in various reactions such as: (a) deoxyribonucleic acid (DNA) synthesis; (b) purine synthesis (formation of glycinamide ribonucleotide and 5-amino-4-imidazole carboxamide ribonucleotide); (c) Generation of formate into formate pool (in addition to utilization of formate); and (d) amino acid interconversions (Institute of Medicine (US), 1998). Dairy products such as yogurt and blue cheese are underestimated sources of folate; the bioavailability and stability in dairy products is much higher than vegetables (Kowalska & Cichosz, 2014). Our initial search for ‘‘folic acid in angiogenesis” resulted in 150 articles, of which 8 met the criteria for our search. Folate plays an essential role in cell division (Audo et al., 2003). Folate deficiency has been implicated in various diseases such as atherosclerosis, neural tube defects, and cancer (Lin et al., 2012). Different studies have demonstrated the anti-angiogenesis effects of FA. FA concentration-dependently decreases DNA synthesis and proliferation in cultured HUVEC (Guariento et al., 2014; Lin et al., 2012). Further analysis demonstrated that FA increased the levels of p21, p27 and p53 protein in these endothelial cells. By knocking down the expressions of P21 and p27, the FA-inhibited thymidine incorporation was completely blocked. FA increases the levels of phosphorylated Src (p-Src) and p-Src-FA receptor (FR) complex in endothelial cells (Huo, Yeh, & Lee, 2015). In addition, FA also increased NF-jB nuclear translocation and binding of p53 promoter. In conclusion, the anti-angiogenic activity of FA could be summed in these steps: FA binds to FR in endothelial cells, which activates the Src/ERK2/NF-jB/p53 signaling pathways. Subsequently, this pathway up-regulates the expression of p21 and p27, and finally resulting in cell cycle arrest in G0/G1 phases. Further studies on the role of FA in endothelial cell migration support its anti-angiogenesis effects. FA inhibits the formation of Lamellipodia, migration and capillary-like tube formation of endothelial cells (Lai et al., 2014; Novakovic, Stempak, Sohn, & Kim, 2006). Treatments with FA increased Src and p190RhoGAP activity, while decreasing RhoA activity in endothelial cells. In contrast, over-expression of a constitutively active RhoA prevented the FA-induced inhibition of migration and capillary-like tube formation of endothelial cells. Thus, FA inhibits cell migration through inhibition of RhoA activity mediated by activation of the FR/Src/ p190RhoGAP-signaling pathways. In another study, further investigations demonstrated how FA inhibits angiogenesis in tumor cells. Folate-conjugated chitosan nanoparticles (FA-CS-NPs)

Vitamin B12 (Cobalamin), a water-soluble vitamin, acts as a cofactor for a critical methyl transfer reaction converting homocysteine to methionine, and converting l-methylmalonyl-coenzyme A (CoA) to succinyl-CoA; which makes an adequate supply of vitamin B12 essential for normal blood formation and neurological function (Institute of Medicine (US), 1998). The main cause of observable B12 deficiency is pernicious anemia; hematological effects of B12 deficiency are indistinguishable from those of folates deficiency (Institute of Medicine (US), 1998). Common sources of B12 for humans include animal foods; in contrast to other vitamin Bs, B12 is not a normal constituent of plant foods except for certain algae (Ford & Hutner, 1955). Our search for ‘‘vitamin B12 in angiogenesis” led to twelve articles, two of which met our criteria. Studies on Vitamin B12 have shown that it closely interacts with metabolism of L-argininenitric oxide (NO) system, essential fatty acids, and eicosanoids that leads to production of NO, prostaglandin E1, prostacyclin, prostaglandin I3, lipoxins, resolvins, protectins, and generation of proinflammatory cytokines leading to angiogenesis (Das, 2015). Vitamin B12 deficiency has also been associated with elevation in homocysteine levels (Yajnik et al., 2006), since vitamin B12 acts as a cofactor in converting homocysteine to methionine (James et al., 2004). Thus, Vitamin B12 deficiency reduces the remethylation of homocysteine via the enzyme methionine synthase and increases the homocysteine levels in plasma (de Jager, 2014). Studies investigating homocysteine (Hcy) have shown that it significantly decreases cell numbers, viability, and induces a G1/S arrest in endothelial cells in the presence of adenosine. Together in combination with Ade, Hcy also decreases endothelial cell migration and suppresses tube-like formation (Zhang et al., 2012). This combination reduces mRNA levels of VEGF, VEGFR1, VEGFR2, and attenuated protein levels of VEGF, ERK1/2 and Akt, giving Hcy significant anti-angiogenic properties (Zhang et al., 2012). These findings demonstrate how B12 could act as a proangiogenesis substance by reducing the level of Hcy in plasma, decreasing its anti-angiogenesis effects (Fig. 3) (Table 1). 4.9. Vitamin C Vitamin C is classified as a water-soluble vitamin, essential for all humans and other mammals that lack the ability to make it from glucose. The term vitamin C refers to ascorbic acid and dehydroascorbic acid (DHA) because both of these exhibit antiscorbutic activity (Monsen, 2000). Two enolic hydrogen atoms give these compounds their acidic character and are responsible for its anti-oxidant functions (Monsen, 2000). The biological functions of ascorbic acid stem from its ability to provide reducing equivalents for a variety of biochemical reactions. Based on its reducing power, this vitamin can reduce physiologically relevant reactive oxygen species (Buettner & Jurkiewicz, 1993). As a result, this vitamin primarily functions as a cofactor for reactions that require a reduced Iron or copper metalloenzyme. It can also act as a protective antioxidant that operates in the aqueous phase both intra- and extra-cellularly (Englard & Seifter, 1986; Netke, Roomi, Tsao, & Niedzwiecki, 1997; Whiteman, Jenner, & Halliwell, 1997). Vitamin C is known as an electron donor for eight human enzymes. Three participate in collagen hydroxylation, two in carnitine biosynthesis, and three in hormone and amino acid biosynthesis. Based on its ability to donate electrons, ascorbic acid

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Fig. 3. Schematic figure of role of vitamin B12 in angiogenesis process.

is an effective antioxidant agent (Monsen, 2000). Around 90% of vitamin C in diet comes from fruits and vegetables such as citrus fruits, tomatoes and tomato juice, and potatoes being major contributors (Sinha et al., 1993). Other sources include brussel sprout, cauliflower, broccoli, strawberries, cabbage, and spinach. The main physical symptom of ascorbic acid deficiency disease, scurvy, a disease that involves deterioration of elastic tissue, illustrates the important role of ascorbate in connective tissue synthesis (Monsen, 2000). Our search for ‘‘ascorbic acid in angiogenesis” resulted in 78 articles, 4 of which met our search criteria. According to studies on effects of ascorbic acid (AA), high concentration of AA alters the metabolic activity of endothelial cells by decreasing ATP levels, and preventing significant cell proliferation without changing cell viability (Mikirova, Ichim, & Riordan, 2008). Additionally, by measurements of wound healing, AA showed a significant decrease in cell migration (Mikirova et al., 2008). Experiments in vitro demonstrated inhibitions of cell structure after long exposure of cells to AA. This appeared to be secondary to inhibition of nitric oxide (NO) production in endothelial cells, which is known as a major stimulus for new blood vessel formation (Gallo et al., 1998; Gratton et al., 2003; Jadeski & Lala, 1999; Lee et al., 1999). High concentrations of AA inhibit NO production, hence limiting angiogenesis and new blood vessel formation (Conejo-Garcia et al., 2004). Overloading of AA affects NO production by changing the oxidative-reduction status inside the cells, which as a result decrease NO availability by formation of peroxynitrite (Mikirova et al., 2008). High concentrations of AA increase the availability of AA radicals, which in turn, increases the reactions between the two (Kytzia, Korth, Sustmann, de Groot, & Kirsch, 2006). In conclusion, high concentrations of AA inhibit angiogenesis by affecting the initial phase of cell migration and tube formation. In addition, ascorbate is involved in different physiological and biochemical processes involving enzymatic reactions catalyzed by members of Fe2+–2-oxoglutarate-dependent family of dioxygenases. These reactions are demonstrated as follow (Englard & Seifter, 1986; Ozer & Bruick, 2007):

Fe3þ  dioxygenaseðinactiveÞ þ AscH ! Fe2þ  dioxygenaseðactiveÞ þ Asc : Ascorbate is essential in maintaining iron in ferrous state, thereby insuring full activity of this class of enzymes (Englard & Seifter, 1986; Ozer & Bruick, 2007). Cytoplasmic prolyl hydroxylases, a novel member of dioxygenases family regulate hypoxiainducible transcription factor (HIF) (Bruick & McKnight, 2001). Since VEGF is a product of HIF-targeted gene (Mole et al., 2009; Semenza, 2003; Semenza, 2012), ascorbate availability impacts cell function such as cell survival and angiogenesis (Du, Cullen, & Buettner, 2012) through ensuring the full activity of HIF-related enzymes, and thereby, influence tumor angiogenesis (Gratton et al., 2003). Investigations on mice have further proven the antiangiogenesis effects of AA. Experiments on mice subjected to a high dose of AA after intraperitoneal administration of sarcoma S-180 cells showed a 20% increase in survival rate of tumor cells (Yeom et al., 2009). The highest survival rate was observed in the group that received continuous injection before and after the injection of cancer cells; suggesting carcinostatic effect induced by high concentrations of ascorbic acid occurred through inhibition of angiogenesis (Yeom et al., 2009) (Fig. 4B).

4.10. Vitamin D Vitamin D, calciferol, contains a group of fat-soluble seco-sterols that could be found in very few foods (Sheibani & D., 2006). Naturally, calciferol is photosynthesized in the skin of vertebrates by reactions made possible by solar UV B radiation (Holick, 1994). Vitamin D comes in many forms, but the two most physiologically significant ones are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) (Holick, 1994). Vitamin D2 originates from yeast and plant sterol, while D3 comes from 7-dehydrocholesterol, a precursor of cholesterol, when synthesized in the skin. Main function of Vitamin D is to maintain serum calcium and phosphorus concentrations within the normal range via increasing

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Fig. 4. Schematic figure of role of vitamins in angiogenesis process. (A) Role of vitamin D in angiogenesis; (B) role of vitamin C in angiogenesis.

the efficiency of small intestine to absorb these minerals from food (DeLuca, 1988; Reichel, Koeffler, & Norman, 1989). The major source of Vitamin D throughout the world is exposure of the skin to sunlight (Holick, 1994). UV B photons with energies

between 290 and 315 nm are absorbed by the cutaneous 7-dehydrocholesterol to form the split (seco) sterol previtamin D (Holick, 2006; MacLaughlin, Anderson, & Holick, 1982). This process occurs in most plants and animals (Holick, 1994).

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Few foods naturally contain vitamin D. These include fish liver oils, the flesh of fatty fish, the liver and fat from aquatic mammals such as seals and polar bears, and eggs (Holick, 1994). Vitamin D deficiency is characterized by inadequate mineralization or demineralization of the skeleton. Vitamin D deficiency in children mainly results in inadequate mineralization of the skeleton, known as osteomalacia, is characterized by widening at the end of the long bones, rachitic rosary, and deformations in the skeleton including frontal bossing (Holick, 2006). Our initial search for ‘‘vitamin D in angiogenesis” identified 220 articles, only 10 qualified for our criteria and concentrated on the mechanisms of vitamin D in angiogenesis. Studies have found anti-proliferative effects of 1,25D3 (active form of vitamin D) on tumor-derived endothelial cells through the induction of cell cycle arrest and apoptosis, demonstrating vitamin D’s anti-angiogenic properties (Chakraborti, 2011). Besides endothelial cells, vitamin D also affects physiological functions and pathology of vascular smooth muscle cells, which includes vascular calcification and cell growth (Bernardi, Johnson, Modzelewski, & Trump, 2002; Chakraborti, 2011). Further studies, especially on tumor cells, have demonstrated that cells express specific nuclear vitamin D receptor or VDR for the active form of the hormone calcitriol (Bernardi et al., 2002). These receptors belong to the superfamily of nuclear receptors which also include receptors for steroid/thyroid hormones (Marcus, 2001). Binding of calcitriol to VDR induces a confrontational change that activates the VDR, which dimerizes with the nuclear retinoic X receptor (Bernardi et al., 2002; Kalkunte, Brard, Granai, & Swamy, 2005). The binding of heterodimers to vitamin D response elements (VDRE) in the promoter of target genes enhance their transcription, which results in alterations of phosphocalcic metabolism or regulation of cell division, differentiation and cell death (Audo et al., 2003). Binding of calcitriol to VDR is identified to regulate more than 60 genes resulting in prodifferentiating, anti-proliferative, and anti-metastatic effects, in addition to effects on cell cycle, and especially anti-angiogenesis activity. Calcitriol interfere with activation, proliferation, migration, and sprouting and tube formation of endothelial cells by participating in various intracellular signaling pathways (Ali & Vaidya, 2007; Bernardi et al., 2002; Kalkunte et al., 2005). Further studies have found that calcitriol inhibits growth of tumor-derived endothelial cells (TDEC) in two tumor models at nano-molar concentrations (Chakraborti, 2011; Kalkunte et al., 2005). This mechanism helps restore the homogeneity of endothelial cells in blood vessel wall and thereby, brings the vessel framework and functionality toward natural cells and hence prevents tumor angiogenesis. Further analysis showed that calcitriol increases the number of VDR and the level of apoptogenic protein p27 (Kip 1) in TDEC, making calcitriol more important in anti-angiogenic and apoptotic effects (Chakraborti, 2011). Investigations on cancer patients have found that 20–60% of cancer patients have insufficient plasma levels of vitamin D (Tomiska, Novotna, Klvacova, Tumova, & Janikova, 2015). Many authors have associated vitamin D deficiency with more aggressive tumors and shorter survival length in cancer patients (Tomiska et al., 2015). Further studies on vitamin D binding protein (DBP-maf) have shown that DBP-maf inhibits human endothelial cell (HEC) proliferation by inhibiting DNA synthesis (Kisker et al., 2003). Usage of DBP-maf significantly induced S- and G0/G1-phase arrest in endothelial cells (Kalkunte et al., 2005). DBP-maf potently blocks VEGF-induced migration and tube formation of endothelial cells in a dose dependent manner (Kalkunte et al., 2005). Additionally, DBP-maf inhibits growth factor-induced microvessel sprouting and VEGF signaling by decreasing VEGF-mediated phosphorylation of VEGFR2 and ERK1/2, a downstream target of VEGF signaling

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cascade (Kalkunte et al., 2005; Kisker et al., 2003). In conclusion, DBP-maf inhibits angiogenesis by blocking critical phases such as proliferation, migration, tube formation and microvessel sprouting of endothelial cells, exerting its effect by inhibition of VEGFR2/ ERK1/2 signaling cascades (Fig. 4A). Work from our laboratory showed calcitriol is a potent inhibitor of retinal neovascularization in vivo and capillary morphogenesis of retinal endothelial cells in culture, and may benefit a variety of eye diseases with a neovascular component (Albert et al., 2007). On the other hand, a study conducted by Jung et al. (2015) on vitamin D3 pre-activated preadipocytes on hair growth resulted in the promotion of hair growth and its regeneration in mice; farther testing showed increased levels of VEGF, suggesting that angiogenesis is involved in the hair formation initiated by conditioned medium from preactivated preadipocytes (Jung et al., 2015). Further signaling studies reveal vitamin D3 enhances the production of VEGF, which is in turn reduced by an ERK1/2 inhibitor, and consequently, the level of ERK1/2 phosphorylation increases by the vitamin D3 treatment. (Table 1). 4.11. Vitamin E Out of the eight naturally occurring forms of Vitamin E, only the

a-tocopherol form of the vitamin is maintained in human plasma (Traber, 1999). Vitamin E acts as a chain-breaking antioxidant, which prevents the propagation of free-radical reactions (Burton, Cheeseman, Doba, Ingold, & Slater, 1983; Burton, Cheng, Webb, & Ingold, 1986; Burton, Joyce, & Ingold, 1983; Kagan & Packer, 1994; Kamal-Eldin & Appelqvist, 1996). The vitamin is a proxyl radical scavenger (Zalkin et al., 1962) and acts as a protector for polyunsaturated fatty acids (PUFA) within membrane phospholipids and in plasma lipoproteins (Burton, Joyce, et al., 1983). In addition, a-tocopherol has specific molecular functions such as inhibition of protein kinase C activity, which is involved in cell proliferation and differentiation of smooth muscle cells (Azzi et al., 1995; Boscoboinik, Szewczyk, & Azzi, 1991; Clement & Bourre, 1997). Most of the dietary vitamin E is found in food containing fat. Vitamin E absorption requires micelle formation and chylomicron secretion by the intestine (Muller, Harries, & Lloyd, 1974). Overt deficiency of Vitamin E is rare, and mostly seen in individuals unable to absorb the vitamin or with inherited abnormalities that prevent the maintenance of normal blood concentrations (Monsen, 2000). Our search for ‘‘vitamin E in angiogenesis” resulted in 58 studies, of which 7 met our criteria and were used here. Investigations on Vitamin E with particular emphasis on Tocotrienol (T3) [a natural analogue of Tocopherol, Toc] has shown antiangiogenic properties. Experiments demonstrated that T3 inhibits both proliferation and tube formation of bovine aortic endothelial cells (De Silva, Chuah, Meganathan, & Fu, 2016). Additionally, experiments on delta-T3 in vivo demonstrated the inhibition of new blood vessel formation (De Silva et al., 2016). Furthermore, atocopheryl succinate (vitamin E succinate [VES]) is identified to have the most pronounced antitumor properties (Savitskaya & Onischenko, 2016). VES has multiple intracellular effects, including induction of apoptosis, inhibition of proliferation, induction of differentiation, and finally resulting in inhibition of angiogenesis (Savitskaya & Onischenko, 2016). These effects are mainly noted in tumor cells rather than normal cells and tissues. Moreover, reports show the ability of T3 to suppress the signaling of growth factor-dependent activation of PI3K/PDK/Akt in neoplastic mammary cells (Miyazawa, Tsuzuki, Nakagawa, & Igarashi, 2004). PI3K, a lipid signaling kinase, activates PDK, leading to the activation of Akt, resulting in phosphorylation of various intracellular substances associated with cell proliferation and apoptosis (Miyazawa et al., 2004; Miyazawa, Tsuzuki, et al., 2004).

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Additionally, different growth factors are closely involved in neovascularization. Activation of endothelial cells by FGF and VEGF results in secretion of proteases and plasminogen activators, which in turn degrade the vessel basement membrane (Savitskaya & Onischenko, 2016). With the critical role of latter mechanism in angiogenesis, it is demonstrated that T3 modulates angiogenesis and works as an antiangiogenic agent (Savitskaya & Onischenko, 2016). Additional examinations have shown that Delta-T3 has the most anti-angiogenic effects among T3 isomers (De Silva et al., 2016). Studies conducted with conditioned medium rich environment on DLD-1-CM have shown the significant suppression

of induced tube formation, migration, and adhesion in HUVEC by delta-T3 (Savitskaya & Onischenko, 2016). These attributes are linked to the signaling pathway PI3K/PDK/Akt as well as induction of stress response in endothelial cells. Furthermore, a mitochondrially targeted analog of a-tocopheryl succinate (MitoVES) has a high propensity to induce apoptosis (Rohlena et al., 2011), resulting in anti-angiogenesis effects (Miyazawa, Shibata, Nakagawa, & Tsuzuki, 2008; Rohlena et al., 2011). MitoVES efficiently kills proliferating endothelial cells and suppresses angiogenesis by inducing accumulation of reactive oxygen species, and induction of apoptosis (Miyazawa et al., 2008) (Fig. 5A).

Fig. 5. Schematic figure of role of vitamins in angiogenesis process. (A) Role of vitamin E in angiogenesis; (B) role of vitamin K in angiogenesis.

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4.12. Vitamin K Vitamin K acts as a coenzyme in the synthesis of biologically active form of a number of proteins that are involved in blood coagulation and bone metabolism. Vitamin K plays a crucial role in the posttranslational conversion of specific glutamyl residues, in a limited number of proteins, to c-carboxyglutamyl (Gla) residues (Suttie & Booth, 2011; Trumbo et al., 2001). Predominant source of vitamin K in North American diet is phylloquinone from green leafy vegetables (Booth & Suttie, 1998). Significant vitamin K deficiency is defined as vitamin K-responsive hypoprothrombinemia and it is associated with an increase in prothrombin time (PT) and, in severe cases, bleeding (Suttie, 1995). Our initial search for ‘‘vitamin K in angiogenesis” led to thirty-seven articles, nine of which met our criteria and are discussed here. Protein S (PS), a vitamin K-dependent glycoprotein, is a prominent anticoagulant and agonist for tyrosine kinase receptors Tyro3, Axl, and Mer (Fraineau et al., 2012). Endothelium expresses these three receptors, Tyro3, Axl, and Mer, and is responsible for producing PS (Sandur, Pandey, Sung, & Aggarwal, 2010). Studies in vivo on PS have demonstrated its anti-angiogenesis effects by inhibiting VEGFR2-dependent vascularization and the capacity of endothelial cells to form capillary-like networks as well as VEGF-induced endothelial cell migration and proliferation (Fraineau et al., 2012). Additionally, PS inhibits VEGF-induced endothelial VEGFR2 phosphorylation and activation of mitogen-activated kinaseErk1/2 and Akt (Na, Han, Park, & Yang, 2013). This study suggests a PS/Mer/SHP2 axis that inhibits VEGFR2 signaling, regulating endothelial cell function, and appointing PS as an endogenous angiogenesis inhibitor (Fraineau et al., 2012). Activation of signal transducers and activators of transcription 3 (STAT3) has been linked to carcinogenesis through promotion of proliferation and angiogenesis of tumor cells (Sandur et al., 2010). Activation of STAT3 regulates the expression of various gene products with significant impact on cell survival, proliferation, and angiogenesis (Aggarwal et al., 2006; Aggarwal et al., 2009; Yu & Jove, 2004). Thus, agents that suppress STAT3 activation have the potential to be used in cancer treatment because of their angiogenesis effects (Sandur et al., 2010). Investigations on 5-hydroxy-2methyl-1,4-naphthoquinone (plumbagin), an analogue of vitamin K isolated from chitrak (Plumbago zeylanica medicinal plant) have demonstrated its effects on modulating the STAT3 pathway (Sandur et al., 2010). Studies showed that plumbagin inhibits both constructive and interleukin 6-inducible STAT3 phosphorylation in multiple myeloma (MM) cells, which correlates with inhibition of c-Src, Janus-activated kinase (JAK)1, and JAK2 activation (Sandur et al., 2010). Further investigations demonstrated that plumbagin suppresses the expression of STAT3-regulated genes, including cyclin D1 (Samykutty et al., 2013) and the antiapoptotic gene products. Suppression of STAT3 by plumbagin can facilitate apoptosis since STAT3 contributes to oncogenesis by protecting cancer cells from apoptosis. This mechanism is linked to downregulation of Bcl-xL expression by plumbagin to induce apoptosis (Sandur et al., 2010). Plumbagin also downregulates the VEGF expression, a critical growth factor of tumors regulated by the STAT3. Further investigations on VK2 have shown its ability to suppress viability of androgen-dependent and androgen-independent prostate cancer cells through caspase-3 and -8 dependent apoptosis (Samykutty et al., 2013; Sandur et al., 2010; Yoshiji et al., 2005). Furthermore, administration of VK2 showed a significant decrease in cell migration and angiogenesis, which could be directly correlated with lower levels of Akt and NF-jB present in these cells. Additionally, menadione (Vitamin K3) decreases the expression of luciferase under the control of hypoxia-responsive element in hypoxic cells (Samykutty et al., 2013). Furthermore, menadione efficiently blocked the interaction between the full-length HIF-1a

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and p300, a mechanism that is engaged in response to hypoxia (Gigante et al., 2015; Samykutty et al., 2013). This mechanism down-regulates the expression of HIF-1a target gene VEGF, thus, working as an anti-angiogenesis factor (Gigante et al., 2015; Na et al., 2013) (Fig. 5B). 5. Conclusions In this review, the pro- and/or anti-angiogenic effects of vitamins (A, B, C, D, E and K) were overviewed. According to the reviewed studies the following conclusions were drawn:  Vitamin A, a fat-soluble vitamin, differs in pro-angiogenic and anti-angiogenic behavior based on its derivative and physiological settings; 13-cis retinoid acid and acyclic retinoid inhibits angiogenesis while ATRA has pro-angiogenesis effects.  Vitamin B1, a water-soluble vitamin, acts as a pro-angiogenic substance through modulation of PKB/Akt pathway.  Vitamin B2, a water-soluble vitamin, inhibits angiogenesis by decreasing phosphorylation of Src tyrosine 16 in tumor cells.  Vitamin B3, a water-soluble vitamin, acts as a pro-angiogenic substance through NAD (+)-dependent, sirtuin (SIRT) mediated responses.  Vitamin B6, a water-soluble vitamin, suppresses the proliferation of endothelial cells and inhibits DNA polymerase and DNA topoisomerases, thus acting as an anti-angiogenic substance.  Vitamin B9, a water-soluble vitamin, acts on anti-angiogenesis by decreasing DNA synthesis and proliferation of endothelial cells.  Vitamin B12, a water-soluble vitamin, is pro-angiogenesis by inducing production of NO and decreasing homocysteine levels in plasma.  Vitamin C, a water-soluble vitamin, is anti-angiogenesis by inhibiting NO production.  Vitamin D, a fat-soluble vitamin, acts as an anti-angiogenic substance through the induction of cell cycle arrest and apoptosis of vascular and tumor cells.  Vitamin E, a fat-soluble vitamin, works as anti-angiogenic substance by inhibiting both proliferation and tube formation of endothelial cells.  Vitamin K, a fat-soluble vitamin, acts as an anti-angiogenic substance through protein S, inhibiting VEGF-R2-dependent vascularization.

Acknowledgments The authors have stated explicitly that there are no conflicts of interest in connection with this article. The work in NS lab is supported by an unrestricted award from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, Retina Research Foundation, P30 EY016665, P30 CA014520, EPA 83573701, EY022883 and EY026078. NS is a recipient of RPB Stein Innovation award. This publication is dedicated to the memory of Dr. H. Afsar Lajevardi (Saghiri & Saghiri, 2017), a legendry Pediatrician (1953–2015) who passed away during this project. We will never forget Dr. H. Afsar Lajevardi’s kindness and support. References Aggarwal, B. B., Kunnumakkara, A. B., Harikumar, K. B., Gupta, S. R., Tharakan, S. T., Koca, C., ... Sung, B. (2009). Signal transducer and activator of transcription-3, inflammation, and cancer: How intimate is the relationship? Annals of the New York Academy of Sciences, 1171, 59–76. Aggarwal, B. B., Sethi, G., Ahn, K. S., Sandur, S. K., Pandey, M. K., Kunnumakkara, A. B., ... Ichikawa, H. (2006). Targeting signal-transducer-and-activator-of-

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