Arterial smooth muscle dynamics in development and repair

Developmental Biology 435 (2018) 109–121

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Arterial smooth muscle dynamics in development and repair a,⁎

Urmas Roostalu , Jason KF Wong

MARK

a,b

a Manchester Academic Health Science Centre, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, School of Biological Sciences, University of Manchester, UK b Department of Plastic Surgery, Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK

A BS T RAC T Arterial vasculature distributes blood from early embryonic development and provides a nutrient highway to maintain tissue viability. Atherosclerosis, peripheral artery diseases, stroke and aortic aneurysm represent the most frequent causes of death and are all directly related to abnormalities in the function of arteries. Vascular intervention techniques have been established for the treatment of all of these pathologies, yet arterial surgery can itself lead to biological changes in which uncontrolled arterial wall cell proliferation leads to restricted blood flow. In this review we describe the intricate cellular composition of arteries, demonstrating how a variety of distinct cell types in the vascular walls regulate the function of arteries. We provide an overview of the developmental origin of arteries and perivascular cells and focus on cellular dynamics in arterial repair. We summarize the current knowledge of the molecular signaling pathways that regulate vascular smooth muscle differentiation in the embryo and in arterial injury response. Our review aims to highlight the similarities as well as differences between cellular and molecular mechanisms that control arterial development and repair.

1. Introduction Most tissues react to injuries by initiating a complex and multifaceted response that involves inflammation and activation of diverse cell types that contribute to the healing process. Several tissues can achieve complete restoration of the damaged architecture by either extensive enrolment of stem cells or proliferation of non-specialized cell types. Controversial hypothesis suggests that in some cases adult tissue regeneration recapitulates embryonic developmental mechanisms. Arterial response to injury involves several distinct cell types and although the repair process is efficient, it often results in excessive cell proliferation in the vascular wall that can eventually reduce blood flow and lead to vascular occlusion. The current review aims to provide an overview and compare the mechanisms that regulate vascular smooth muscle differentiation in embryonic development and arterial injury repair. In addition we discuss here why the principal developmental processes that control arterial morphology fail in arterial injury repair and how the knowledge of these mechanisms may offer new opportunities to treat cardiovascular diseases. 2. Cellular architecture of arterial walls The primary cell types of arterial walls, endothelial cells and vascular smooth muscle cells (VSMCs), have been described since the

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19th century. In recent years a great number of additional cell types have been identified, revealing an elaborate morphology of large blood vessels (Fig. 1A). The arterial lumen is covered by a layer of endothelial cells that in addition to providing the primary barrier also secrete vasodilators (i.e. nitric oxide) and vasoconstrictors (i.e. endothelin-1). A thin basement membrane separates the endothelium from the surrounding tunica intima. Here a distinct layer of pericyte-like cells forms an interconnected network adjacent to the endothelium (Andreeva et al., 1998; Orekhov et al., 2014; Rekhter et al., 1991). The role of these intimal pericytes remains to be established, but they have been postulated to contribute to atherosclerosis by modifying the local inflammatory microenvironment (Ivanova et al., 2015). The majority of the tunica intima is composed of a proteoglycan rich matrix with embedded immature VSMCs (Glukhova et al., 1988; Orlandi et al., 1994). At aortic branch sites a specific population of VSMCs develops early in the embryo and are maintained in immature state until adulthood (Roostalu et al., 2017). These cells make up cushion-like structures at branching sites, but little is known about their function. Intimal cushions have been proposed to play a role in directing blood cells to lateral branches (Fourman and Moffat, 1961), but they may in addition provide strength to the branching sites that are influenced by blood flow turbulences and may even represent a pool of immature cells that can contribute VSMCs to growing arteries. Importantly, arterial branching sites are prone to developing athero-

Corresponding author. E-mail addresses: [email protected] (U. Roostalu), [email protected] (J.K. Wong).

https://doi.org/10.1016/j.ydbio.2018.01.018 Received 25 November 2017; Received in revised form 8 January 2018; Accepted 24 January 2018 Available online 15 February 2018 0012-1606/ © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).

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Fig. 1. Cellular composition and developmental origin of arteries. A, Schematic cross section of aorta, demonstrating distinct cell types in the vascular wall. B, Developmental origin of VSMCs in mouse arteries. The current understanding of VSMC embryonic origin is extrapolated on adult mouse vasculature with the color scheme indicating the embryonic source. The right subclavian artery arises from pharyngeal arch artery, which recruits neural crest cells to VSMC fate. The left subclavian derives from the descending aorta, which recruits mesodermal cells to VSMC differentiation. VSMCs in many arteries originate from multiple cell types. In many internal organs they can arise from somitic mesoderm as well as mesothelial cells. In coronary arteries both proepicardium and endothelial cells contribute to the smooth muscle layer.

Pasquinelli et al., 2007; Passman et al., 2008; Sainz et al., 2006; Zengin et al., 2006). Several lines of evidence suggest that there are even more multipotent progenitor cells in the adventitia. A sub-population of adventitial cells expresses markers of mesenchymal stromal cells (CD44 and CD90) (Corselli et al., 2012; Klein et al., 2011). As CD34+ adventitial cells also upregulate these stromal cell markers in vitro (Campagnolo et al., 2010; Hoshino et al., 2008; Pasquinelli et al., 2007), it is possible that they represent the same linage at different stages of activation and differentiation. These stromal-like cells are capable of VSMC, chondrogenic and adipogenic differentiation (Corselli et al., 2012; Hoshino et al., 2008). The development of adventitial cells relies on Sonic Hedgehog signaling and hence one of the most promising genes to identify this cell population is GLI1, a Sonic Hedgehog pathway transcription factor (Kramann et al., 2015; Passman et al., 2008). GLI1+ cells express typical adventitial markers SCA1, CD34 and to a variable degree diverse mesenchymal stromal cell (CD29, CD44, CD90) as well as immature VSMC markers, indicating possible lineage continuity between adventitial cells. GLI1+ cells can differentiate into VSMC, fibroblasts and osteoblast-like cells (Kramann et al., 2016). There are also progenitor/stem cells in the tunica adventitia that are characterized by the expression of SRY-Box 10 (SOX10), SOX17, S100β as well as mesenchymal stromal markers CD44 and CD29, but lacking in CD31, CD34, CD146 and SCA1. This cell population, in vitro, can be differentiated into VSMCs, Schwann cells, peripheral neurons, chondrocytes, osteoblasts and adipocytes (Tang et al., 2012). A dense capillary network of vasa vasorum surrounds larger human arteries to supply blood to the adventitia and tunica media. Hence, endothelial cells and associated pericytes are found frequently in the adventitia. Pericytes can be distinguished by Neural-glial antigen 2 (NG2) and CD146 expression and in vitro can differentiate into VSMCs as well as various mesenchymal cell types (Billaud et al., 2017; Crisan et al., 2008). In vivo plasticity of pericytes has remained difficult to establish due to the lack of specific lineage tracing transgenic

sclerotic lesions, demonstrating their importance in the context of cardiovascular medicine (VanderLaan et al., 2004). The outer section of the tunica intima is composed of elastic fibers and spindle-shaped contractile VSMCs (Rekhter et al., 1991). It is separated from the overlying tunica media by internal elastic lamina. The tunica media is the most prominent part of the arterial wall and is made of concentric layers of mature VSMCs. The elastin-based matrix that surrounds VSMCs enables expansion and contraction of large arteries during systole and diastole. The relative abundance of collagen and other extracellular matrix molecules to elastin and particularly the architecture in which they pattern the vessels define the biomechanical properties of arteries (Cheng and Wagenseil, 2012). Tunica media is enclosed by loosely packed adventitial layer that harbors several distinct cell types. Our current understanding of the tunica adventitia composition is still often limited to identifying cells by relatively non-specific surface markers, making it impossible to distinguish discrete cell lineages from distinct differentiation stages of a single cell lineage. The most widely accepted markers for adventitial cells are SCA1 (Stem cell antigen-1) and CD34 that identify cells around most mouse arteries (Hu et al., 2004; Passman et al., 2008). Similar CD34+ cells are enriched at the interface of tunica media and tunica adventitia in human arteries (Invernici et al., 2007; Zengin et al., 2006). Intriguingly, Sainz et. al. found SCA1+ cells in the tunica media (Sainz et al., 2006), suggesting that adventitial cells are capable of penetrating deeper into the arterial wall or there are progenitors of adventitial cells that arise from VSMCs (discussed below). Typical adventitial cells are in a poised state of smooth muscle differentiation as they lack characteristic VSMC markers, but express both transcriptional activators and repressors of VSMC differentiation (Passman et al., 2008). Consequently, activation of these cells for example in vitro or in transplantation to vein grafts leads to VSMC differentiation (Hu et al., 2004; Passman et al., 2008; Shen et al., 2016). In addition to smooth muscle differentiation these cells can in vitro commit to endothelial cell fate (Hu et al., 2004; Invernici et al., 2007;

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At the onset of vascular development numerous branches arise from the aortae. Six pairs of pharyngeal arch arteries (the 5th pair forming only partly) arise from the cardiac outflow tract and connect to the dorsal aortae. In the course of rapid morphological changes the anterior pharyngeal arch arteries give rise to the major blood vessels that provide blood to the cranial and anterior part of the body. The right subclavian artery originates from the right fourth pharyngeal arch artery, whereas the left subclavian branches out directly from the descending aorta. Large-scale remodeling of the pharyngeal arch arteries is completed by E12.5 in the mouse embryo (42–44 days in humans) (Hiruma et al., 2002). At this time the left of the paired dorsal aortae develops into the aortic arch and the descending aorta whereas the right one largely regresses. Intersomitic vessels branch out from the aortae in dorsal direction and develop in cranio-caudal manner as the somites form, starting around E8.5. The first five branches are transient and form the vertebral artery that gives rise to the vasculature of the midbrain and hindbrain. The intersomitic vessels between the trunk somites are long-lived and form a dense vascular plexus around the neural tube (Walls et al., 2008). In the posterior region the paired dorsal aortae start to fuse at the midline around E9.5. Various branches stem from the abdominal aorta to deliver blood to internal organs.

models. A recent study used Tbx18 (T-box 18) -CRE-ERT2 mouse line to map the fate of pericytes. While the isolated cells gave rise to diverse cell lineages in vitro the cells maintained their perivascular identity in vivo even when exposed to tissue injury (Guimaraes-Camboa et al., 2017). This raises the possibility that the in vivo niche of these cells is sufficient in preventing their differentiation into other cell types. Alternatively, current evidence does not rule out that other subsets of perivascular cells, not marked by Tbx18 expression, can act as tissue resident progenitor cells in vivo. Mesoangioblasts represent a subset of perivascular cells of the aorta and can also be induced to differentiate into diverse lineages, including skeletal muscle cells (Dellavalle et al., 2007; Minasi et al., 2002). Perivascular adipose tissue surrounds and cushions the artery outside the adventitial layer and has also an important functional role. The composition of the adipose deposit varies between mouse arteries: the abdominal aorta is enwrapped by a mixture of brown and white adipocytes; the mesenteric arteries primarily by white adipose tissue; the thoracic aorta by brown adipocytes; whereas the coronary arteries appear to lack adipose layer. Most human arteries are covered by adipose tissue made of both brown and white adipocytes (Brown et al., 2014). Perivascular adipocytes are increasingly recognized as important mediators of vascular function and secrete a wide variety of signaling molecules that often enhance vasodilation and include adiponectin, H2S, angiotensin-(1−7), palmitic acid methyl ester and prostacyclin (Chang et al., 2012; Fesus et al., 2007; Greenstein et al., 2009; Lee et al., 2009, 2011; Lohn et al., 2002; Soltis and Cassis, 1991; Wojcicka et al., 2011). Adipocytes can also potentiate VSMC contraction by producing angiotensin II and superoxide (Gao et al., 2006; Lu et al., 2010; Owen et al., 2013; Ramirez et al., 2017). In addition to regulating vasoconstriction, perivascular adipocytes play a role in controlling intravascular temperature (Chang et al., 2012) and secrete a large number of cytokines and growth factors that may influence cell turnover and differentiation in the arterial wall (Nosalski and Guzik, 2017). Finally, arteries are richly innervated to modulate vascular tone. Unlike in the skeletal muscle there are no direct synaptic contacts to VSMCs and neurotransmitters are released to the extracellular space in the adventitia from where they diffuse to VSMC (Westcott and Segal, 2013).

4. Embryonic origin of vascular wall cells Arterial vasculature arises from extensive remodeling of primitive blood vessels alongside the development of surrounding tissues that influence its differentiation and cellular composition. The early dorsal aortae are initially simple endothelial tubes that acquire VSMCs after E9.5 (Takahashi et al., 1996). VSMCs are recruited from the adjacent tissues as the arterial network forms and as such their origin varies depending on the anatomical location of the blood vessel (Fig. 1B). VSMCs in the pharyngeal arch arteries as well as their derivatives arise from the neural crest. The VSMCs of the arteries in the adult forebrain as well as ventral and anterior structures of the face hence originate from the neural crest. In contrast, cerebellar and occipital arteries that stem from the vertebral arteries and develop from intersomitic vessels lack neural crest derived VSMCs. Neural crest cells provide VSMCs also to the medial layer of the ascending aorta and limited parts of coronary arteries where they arise from the aorta (Bergwerff et al., 1998; Etchevers et al., 2001; Jiang et al., 2000). VSMCs in the right, but not in the left subclavian artery are of neural crest origin (Jiang et al., 2000). Curiously, within the same vessel, where neural crest derived VSMC make up the majority of the tunica media such cells are less frequent in the tunica intima (Bergwerff et al., 1998), highlighting their possibly distinct origin. Additional lineage tracing studies with transgenic animal models are needed to confirm these observations. Mesoderm represents the second major source of VSMC. Mesodermal secondary heart field derived cells populate the outer medial layer of the ascending aorta, signifying their arrival after neural crest derived cells (Sawada et al., 2017). The embryonic secondary heart field that forms the outflow tract generates also most of the VSMCs at a narrow intermediate zone between the myocardium, the aorta and pulmonary trunk (Waldo et al., 2005). Mesothelium is a simple epithelial cell layer surrounding organs in the body cavity and giving also rise to the epicardium. VSMCs in the tunica media of the coronary arteries arise from proepicardiac progenitor cells (Cai et al., 2008; Dettman et al., 1998; Gittenberger-de Groot et al., 1998; Mikawa and Fischman, 1992). Intimal VSMCs in these arteries have not been studied in detail, but may not share proepicardiac origin (Mikawa and Fischman, 1992). In the development of coronary arteries endothelial cells differentiate into a subset of VSMCs as well as giving rise to cardiac pericytes, highlighting the developmental diversity of perivascular cells in the heart (Chen et al., 2016). VSMCs in internal organs are similarly of heterogeneous origin. In early embryonic development (around E8.5 in mouse), even before the lungs form, cardiopulmonary progenitors arise from the secondary

3. Developmental origin of arteries The diverse cell populations in arterial walls have distinct developmental origins that are fundamentally influenced by the anatomical changed that occur during the development of arteries in the embryo. At the onset of the development of the cardiovascular system the primitive heart tube is shaped by E8 (embryonic day 8 in mouse) and undergoes complex morphological changes to form the atrium and ventricle by E9, followed by their subsequent separation into left and right compartments in the next 48 h (Lin et al., 2012). The formation of major blood vessels occurs in parallel with heart development and is initiated by arrangement of endothelial progenitors into string-like structures on both sides of the embryo, laying the foundation for the two dorsal aortae (Drake et al., 1997). At E8 the aortae lack a lumen but rapidly establish one by E8.25 in a process that is mediated by asymmetric localization of antiadhesive CD34-sialomucins between adjacent endothelial cells and concurrent reorganization of the cytoskeleton (Strilic et al., 2009). The initial development of the aortae is guided by NOTCH, vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP) signaling. The paired aortae are kept separated by secretion of BMP antagonists, Noggin and Chordin, from midline localized notochord (Reese et al., 2004). As the development proceeds the aortae move closer towards the midline and recruit endothelial progenitor cells from somitic mesoderm to their dorsal poles. The early lateral plate mesoderm derived cells are gradually restricted to ventral poles of the aortae, where they eventually will give rise to hematopoietic stem cells (Bertrand et al., 2010; Boisset et al., 2010; Chen et al., 2009; Zovein et al., 2008). 111

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heart field and differentiate into various cells of the cardiac inflow tract as well as most mesodermal cell types of the lung, including VSMCs (Peng et al., 2013). Remarkably, in the postnatal growth period, mesothelium derived cells differentiate extensively into VSMCs of the lung (Dixit et al., 2013; Que et al., 2008) as well as many other intestinal organs (Rinkevich et al., 2012; Wilm et al., 2005). VSMCs in the descending aorta are more homogenous in origin. The first VSMCs that differentiate at the ventral pole of the descending aorta, between E9 and E9.5 in mouse, originate from lateral plate (Hungerford et al., 1996; Wasteson et al., 2008). Rapid morphological changes result in these cells being replaced by E11.5 by somite derived mesodermal cells (Esner et al., 2006; Wasteson et al., 2008). After VSMCs are recruited to the arterial wall in early embryonic development, they proliferate extensively. During this brief period the immature VSMCs establish cell lineages that persist to adulthood and there appears to be no, or very limited recruitment of new cells to the aortic wall in the late fetal and postnatal period (Roostalu et al., 2017). Tunica adventitia develops significantly later than other arterial wall cell layers. SCA1+ cells appear first by late embryonic stage (E15.5E18.5 in mouse) (Passman et al., 2008). The adventitial cells have heterogeneous origins. Some adventitial cells in the chick coronary arteries are of neural crest origin, similar to the VSMCs in these blood vessels (Bergwerff et al., 1998). In contrast, SCA1+ adventitial cells do not arise from the neural crest in any of these arteries in mouse (Passman et al., 2008). At least some adventitial cells share a proepicardiac origin with VSMCs in the coronary arteries (Gittenberger-de Groot et al., 1998). Recently, it has been demonstrated that mature VSMCs in numerous arteries, including the aorta, femoral and carotid arteries, give rise to a fraction of SCA1+ adventitial cells (Majesky et al., 2017), supporting cellular lineage continuity between the tunica adventitia and the tunica media. The developmental origin of perivascular adipocytes has yet to be characterized. In other adipose deposits a subset of microvascular pericytes and even endothelial cells may function as adipocyte progenitors (Gupta et al., 2012; W. Tang et al., 2008). The developmental origin of pericytes is similarly heterogeneous, but in many tissues share similarities with VSMCs. Pericytes that line the microvasculature of the head and the central nervous system are of neural crest origin (Etchevers et al., 2001; Heglind et al., 2005; Korn et al., 2002). Pericytes in the eye (including in the optic nerve vasculature) (Trost et al., 2013) and thymus (Foster et al., 2008; Muller et al., 2008) also develop from neural crest progenitors. In contrast, pericytes in the intestine, lung and liver develop from mesothelial cells (Asahina et al., 2011; Que et al., 2008; Wilm et al., 2005) and those in the heart originate from epicardiac progenitors (Cai et al., 2008; Dettman et al., 1998; Mikawa and Gourdie, 1996; Zhou et al., 2008), but also from the endothelium (Chen et al., 2016).

Recently Yamazaki et al. revealed how skin resident myeloid progenitors differentiate into dermal pericytes (Yamazaki et al., 2017). Pericytes in the developing descending aorta and limbs originate from the sclerotomal compartment of the somite (Pouget et al., 2006). Collectively these studies indicate that in most organs pericytes and VSMCs share a common origin, raising the question of the extent in which these cell lineages differ. A better understanding of the embryonic lineage relationship between these two cell types was established in the study of Volz et al. By combining clonal analysis of epicardium derived cells in the mouse heart with genetic lineage tracing using the NG2-CRE-ER model the authors demonstrated that coronary artery VSMC arise from pericyte-like progenitor cells (Volz et al., 2015). Previous in vitro studies also showed that embryonic stem cell derived clones, induced to VSMC differentiation, switch first on pericyte marker genes before upregulating mature VSMC markers. The early induction of pericyte marker genes relies on a different molecular mechanism that likely does not depend on CArG DNA element that recruits transcription factors to the promoters of genes expressed by VSMC (discussed below) (Lindskog et al., 2006). These data suggest that VSMCs may always transit through a pericyte-like state in their differentiation. Bearing this in mind it would be important to determine whether pericytes maintain this capacity in arterial injury response. In summary, extensive fate-mapping studies demonstrate highly heterogeneous origins of VSMCs and other arterial wall resident cells. A number of important questions remain unanswered. For instance, long-term fate mapping experiments are needed to reveal the extent of cell turnover between intimal, medial and adventitial cell layers in normal physiology, aging and in vascular repair. In addition, little is known on how different embryonic origins of vascular smooth muscle cells affect their functional properties and susceptibility to cardiovascular diseases. 5. Molecular mechanisms of VSMC differentiation Molecular regulation of VSMC differentiation has been the focus of extensive research spanning several decades. We provide here a brief overview, focusing on novel findings and those directly related to arterial repair. The recruitment of progenitor cells to blood vessel wall and proliferation of VSMCs in embryonic development is regulated by a number of growth factors (Fig. 2). Platelet derived growth factor B (PDGF-B, functioning as dimer PDGF-BB) is secreted by endothelial cells in growing capillaries and immature arteries, whereas its receptor is expressed in VSMCs and pericytes. Endothelial derived PDGF-BB acts as a chemoattractant to VSMC and pericyte progenitors, and stimulates their proliferation (Hellstrom et al., 1999; Lindahl et al., 1997). Such directional activity of endothelial cells requires polarity

Fig. 2. Molecular regulation of VSMC differentiation. A simplified schematic demonstrating the key pathways that control the recruitment of VSMC progenitors and their subsequent differentiation. Endothelial cells induce the proliferation and recruitment of immature VSMCs by PDGF-BB secretion. TGFβ initiates VSMC differentiation by SMAD dependent transcription of Myocd. Epigenetic modifier TET2 induces 5-hydroxymethylcytosine (yellow) accumulation at Myocd promoter, enabling its transcription. Contractile protein expression is controlled by binding of SRF and MYOCD at CArG motif on the promoter regions. PTEN stabilizes the complex. NOTCH3 ligand JAG1 promotes differentiation. NOTCH intracellular domain interacts with YAP1. Transcription factors HES and HEY mediate gene expression changes downstream of NOTCH. MRTF transcription factors have similar roles to MYOCD. TGFβ dependent SMAD transcription factors are recruited to SMAD binding elements (SBE) to enhance smooth muscle differentiation and can form complexes with MYOCD and ZEB1. Several negative regulators for VSMC differentiation have been identified, among them KLF4 and ELK1 that are in turn repressed by miRNAs miR-143 and miR-145. MCAM/ CD146 regulates VSMC proliferation and differentiation and inhibits premature cell differentiation.

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iator YAP1 (Yes associated protein kinase 1) forms a complex with NOTCH intracellular domain in VSMCs and is recruited to Jag1 promoter. YAP1 is required for initiating the expression of NOTCH target genes and for VSMC differentiation (Manderfield et al., 2015). On the contrary, YAP1 can also repress VSMC differentiation. Arterial injury triggers phenotypic switching of VSMCs to a proliferative state. The redifferentiation of these cells is inhibited by YAP1, which binds to MYOCD and impairs its transcriptional activity (Xie et al., 2012). YAP1 is also a transcriptional activator of CD146 (Wang et al., 2015). We recently found that CD146 is highly expressed in immature VSMCs of the embryo. Its expression is postnatally maintained within intimal VSMCs at the branching sites of the aorta and in the VSMCs of smaller arteries. Intriguingly, the arterial branching sites also maintain YAP1 activity. CD146 is an inhibitor of VSMC differentiation as its knockout enhances contractile protein expression at the same time limiting cell proliferation (Roostalu et al., 2017). CD146 functions as a co-receptor for PDGFRβ and is required for the establishment of pericyte coverage of the capillaries in the brain (Chen et al., 2017). Moreover, CD146 can bind a range of other growth stimulatory molecules, including WNT1, WNT5A, S100A8/A9 and VEGF (Jiang et al., 2012; Ruma et al., 2016; Ye et al., 2013). These data collectively suggest that CD146 has a central role in translating extracellular signals to regulate the fine balance between VSMC differentiation and proliferation. The transcription of many smooth muscle proteins depends on SRF binding to CArG [CC(AT-rich)6GG] elements in their genomic regulatory regions (Miano, 2003). Since SRF is expressed in a wide variety of cell types additional mechanisms control the specificity of VSMC differentiation. In early embryonic development PITX2 (Paired Like Homeodomain 2) protein is recruited to smooth muscle gene promoters, where it enhances SRF-dependent transcription. Lack of PITX2 in mouse impairs VSMC differentiation (Shang et al., 2008). MYOCD is a highly potent activator of SRF in VSMCs and its elimination results in impaired VSMCs differentiation and early embryonic lethality (Li et al., 2003; Long et al., 2007; Miano, 2015; Wang et al., 2001, 2003; D.Z. Wang et al., 2002; Yoshida et al., 2003). Both MYOCD and SRF can interact directly with SMAD3, enabling them to enhance TGFβ signaling (Qiu et al., 2003, 2005). Myocardin related transcription factors A and B (MRTFA/B) are similarly highly expressed in VSMCs and required for the potentiation of SRF-dependent transcription and smooth muscle differentiation (Du et al., 2004; Li et al., 2005; Oh et al., 2005; D.Z. Wang et al., 2002). Separate transcriptional switches control VSMC plasticity and transition of differentiated cells into proliferative cells. Growth factors lead to the DNA recruitment of myogenesis repressor ELK-1 (ETS domain-containing protein Elk-1), which competes with and replaces MYOCD at smooth muscle specific gene promoters, thereby inhibiting differentiation (Wang et al., 2004). Another member of the SRF-myocardin complex is lipid and protein phosphatase PTEN (Phosphatase and tensin homolog), which can stabilize the complex in the nucleus without itself binding to DNA. PDGF-BB signaling causes nuclear exit and degradation of PTEN-SRF complex and accumulation of free SRF in the nucleus, where it can induce the expression of proliferation associated genes together with ELK-1 (Horita et al., 2016). In accordance, loss of PTEN leads to enhanced VSMC proliferation and neointima formation following arterial injury (Furgeson et al., 2010), whereas adenoviral delivery of PTEN inhibits the process (Huang et al., 2005). VSMC differentiation and plasticity are additionally controlled by non-coding regulatory RNAs and epigenetic chromatin modifications that have been covered in separate in depth reviews (Liu et al., 2015; Small and Olson, 2011; Uchida and Dimmeler, 2015; Yu and Li, 2014). The best studied microRNAs (miRNAs) are miR-145 and miR-143 that are direct transcriptional targets of SRF and MYOCD and are induced by TGF-β exposure. These miRNAs have central significance in modulating VSMC differentiation (Cordes et al., 2009; Xin et al., 2009). The effect is on one hand achieved by miR-143 targeting Elk1 and miR-145 targeting Klf4 (Kruppel-like factor 4) (Cordes et al.,

and indeed PDGF-BB secretion is limited to the basal side of endothelium (Zerwes and Risau, 1987). Insulin like growth factor 1 enhances cell proliferation (Clemmons, 1985; Grant et al., 1994), acting synergistically with PDGF-BB (Stiles et al., 1979). Transforming Growth Factor β (TGFβ) is among the most potent inducers of VSMC differentiation in vitro and in vivo (Guo and Chen, 2012). Loss of TGFβ signaling is embryonic lethal and in addition to causing severe angiogenesis defects impairs the development of several other tissues. Knockout of TGFβ binding protein Endoglin leads to more specific defects in VSMC differentiation (Li et al., 1999). Furthermore, ablation of TGFβRII in VSMCs impairs the development of the thoracic aorta (Langlois et al., 2010). TGFβ pathway transcription factors SMAD2/3/4 (SMAD family members 2/3/4) bind directly on the regulatory elements of Myocd (Myocardin), one of the central transcriptional regulators of the VSMC lineage (Davis-Dusenbery et al., 2011a). In addition they enhance the expression of smooth muscle contractile proteins and activate their expression together or independently of MYOCD (Guo and Chen, 2012; Hautmann et al., 1997; Qiu et al., 2003, 2005; Xie et al., 2013). SMADs are often recruited to multimeric protein complexes that stabilize their transcriptional activity. In VSMCs ZEB1 (Zinc Finger E-Box Binding Homeobox 1) binds both SMAD3 as well as SRF (Serum Response Factor), leading to enhanced VSMC differentiation (Nishimura et al., 2006). NOTCH pathway has a central role in embryonic VSMC differentiation. At an early stage, NOTCH signaling induces the commitment of PAX3+ somite cells to VSMC/endothelial fate over a skeletal myogenic fate (Mayeuf-Louchart et al., 2014). The typical NOTCH pathway ligands (Delta Like Canonical NOTCH Ligands 1 and 4 (DLL1, DLL4), Jagged 1 and 2 (JAG1 and JAG2)) are expressed by endothelial cells whereas receptors NOTCH1 and 3 are abundant in embryonic perivascular cells. Endothelial expressed JAG1 activates NOTCH3dependent VSMC differentiation, leading to subsequent JAG1 expression in VSMCs (Liu et al., 2009; Manderfield et al., 2012). This signal amplification mechanism is particularly significant in the construction of multi-layered arterial walls, where overlying layers of VSMCs are successively further away from endothelial ligands (Manderfield et al., 2012). Inactivation of JAG1 in endothelial cells impairs VSMC differentiation, demonstrating the importance of endothelial cells in influencing early VSMC fate (High et al., 2008). Similarly, NOTCH pathway abrogation in neural crest cells inhibits VSMC differentiation and leads to severe cardiovascular defects (High et al., 2007). Inactivation of the pathway in epicardium-derived cells likewise leads to severe vascular abnormalities in the coronary arteries. Presumptive VSMC progenitors accumulate around the forming blood vessels failing to differentiate. On the contrary, conditional activation of NOTCH signaling in epicardium derived cells leads to premature VSMC differentiation (Grieskamp et al., 2011). These data demonstrate a central role for NOTCH in controlling VSMC differentiation. Distinct pairs of NOTCH receptors and ligands regulate VSMC differentiation in different arteries and developmental stages. For example, VSMC differentiation in various arteries depends primarily on NOTCH3 that appears to be dispensable in the aorta (Domenga et al., 2004). The downstream molecular mechanisms by which NOTCH regulates VSMC differentiation are complex and likely very dynamic. On one hand NOTCH can directly induce smooth muscle alpha actin (Noseda et al., 2006; Y. Tang et al., 2008) and PDGFRβ expression (Jin et al., 2008). On the other hand NOTCH pathway transcriptional mediator HEY2/ HRT2 (Hes Related Family BHLH Transcription Factor With YRPW Motif 2) represses the expression of VSMC contractile proteins (Proweller et al., 2005) and inhibits the binding of the NOTCH intracellular domain containing complex on smooth muscle alpha actin promoter (Y. Tang et al., 2008). It appears that a delicate regulatory feedback loop is built into NOTCH signaling that can help to limit the contractile protein expression levels. HIPPO pathway regulates diverse biological processes from mechanotransduction to cell differentiation. HIPPO transcriptional med113

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endothelial cells. VSMC or neural crest specific elimination of GATA6 leads to impaired development of the cardiac outflow tract and the aortic arch (Lepore et al., 2006). Whether GATA6 is required for VSMC differentiation has been difficult to establish due to possible redundancy between GATA factors. Recent study however proposes that GATA6 can act as an activator for Myocd expression in neural crest derived VSMC progenitors in the pharyngeal arch arteries, promoting the establishment of VSMC coverage and survival of the posterior arteries (Losa et al., 2017). Endothelial derived endothelin 1 is another regulator of arterial morphogenesis and acts on the endothelin A receptor on neural crest derived progenitor cells. While it is not necessary for the initial recruitment of VSMCs to the arteries it is required for the subsequent maintenance and patterning of the arterial network (Kim et al., 2013; Kurihara et al., 1995; Yanagisawa et al., 1998). VSMC differentiation has to be tightly controlled to enable the development of the proper architecture of the vascular tree. An elegant example for such regulatory mechanism is dependent on the transcription factor PBX1 (PBX Homeobox 1) that inhibits the expression of PDGFRβ. Genetic elimination of PBX1 from renal arterial VSMC progenitors results in their enhanced differentiation, consequently leading to aberrant and excessive branching of renal arterial network (Hurtado et al., 2015). From the accumulating data it becomes evident that in contrast to several other cell types VSMC differentiation is not controlled by precise binary switches, but rather by dynamic modulation of a set of core regulatory transcription factors and non-coding RNAs that determine the abundance of contractile proteins in the cell and thereby its functional phenotype. Such intrinsic plasticity underlies the capacity of VSMCs to rapidly return to proliferative phenotype upon external injury induced signals.

2009). As described above, ELK1 is an inhibitor of VSMC differentiation and prevents the activity of MYOCD. KLF4 is also a potent repressor of VSMC differentiation program as it limits Myocd expression and MYOCD/SRF complex DNA recruitment (Adam et al., 2000; Liu et al., 2005). The role of KLF4 is multifaceted and context dependent as it can in addition inhibit cell proliferation by inducing the expression of p21 (Autieri, 2008). KLF4 regulates arterial injury response and its elimination leads to enhanced intimal hyperplasia (Yoshida et al., 2008). It is additionally involved in phenotypic switching of VSMCs in atherosclerosis (Shankman et al., 2015). Intriguingly, in addition to targeting Klf4, mir-145 can at least in vitro also act as a positive regulator of Myocd (Cordes et al., 2009). Thus, at the onset of progenitor cell commitment to VSMC differentiation miR145 may enhance MYOCD activity, whereas at late stages both miR143 and miR-145 maintain the contractile phenotype by inhibiting genes associated with VSMC switching to proliferative phenotype. Several independent knockout mouse models have been established for these miRNAs. All of these models are viable and do not show gross morphological defects (Boettger et al., 2009; Elia et al., 2009; Xin et al., 2009). The main defect manifests in thinner arterial walls and a shift towards more immature VSMC phenotype. There is also impaired blood pressure regulation (Boettger et al., 2009; Elia et al., 2009; Xin et al., 2009). Boettger et al. showed that the impaired VSMC differentiation led to spontaneous development of neointimal lesions (Boettger et al., 2009). In line with this notion, overexpression of these miRNAs prevented intimal hyperplasia following carotid artery balloon induced injury (Elia et al., 2009). TGFβRII was recently found to be another target of miR-145 and consequently miR-145 knockout mouse model showed enhanced angiotensin induced cardiovascular fibrosis, demonstrating another beneficial role for this miRNA in cardiovascular physiology (Zhao et al., 2015). In contrast, Xin et al. proposed that loss of these miRNAs prevents neointima formation following arterial ligation (Xin et al., 2009). The reason for this discrepancy remains to be established, but may be explained by different injury model or transgenic strain background. It highlights the importance of mechanism of injury in dictating the subsequent biological effects. Another downstream target of TGF-β signaling is miR-21. It has been linked with both enhancement and reduction of VSMC differentiation (Davis et al., 2008; Ji et al., 2007; Yang et al., 2012). The exact function of this miRNA remains to be elucidated and may depend on the particular studied VSMC differentiation and arterial injury model. These above described studies provide an example of how non-coding RNAs can influence VSMC differentiation. In recent years numerous other miRNAs have been identified that can enhance or inhibit the process. Less is known about epigenetic modulation of VSMC differentiation. Among the epigenetic modifiers of particular significance is the discovery Ten-Eleven Translocation-2 (TET2) as a master regulator of VSMC differentiation. It occupies the regulatory elements of Srf, Myocd as well as Myh11 (encoding for smooth muscle myosin) and is both sufficient and required to initiate VSMC differentiation. Hence, loss of TET2 inhibits the expression of these genes, leading to proliferative and undifferentiated phenotype of VSMCs (Liu et al., 2013). TET2 expression is however not specific to VSMCs and its activity is likely regulated by other co-factors. The above described signaling pathways are not only important in VSMC differentiation but also in defining the morphology of the whole arterial network. The molecular mechanisms that regulate arterial branching are still poorly understood. On one hand endothelial cell responsiveness to external signals controls the branching process, but on the other hand the maintenance of the developed branches relies on tightly regulated establishment of VSMC coverage (Waldo et al., 1996). Defects in the above described genes that control VSMC differentiation impair the morphogenesis of the arterial tree. In addition, transcription factor GATA6 is an important regulator of VSMC-dependent arterial morphogenesis. It induces the expression of semaphorin 3C which in turn influences the migration of both VSMC progenitors as well as

6. Cellular response to arterial injury Once the arteries are fully formed there is very limited VSMC turnover. Mature VSMCs are enriched in contractile proteins, proliferate at a low level and have a half-life of 270–400 days in the mouse aorta (Cook et al., 1994; Neese et al., 2002; Roostalu et al., 2017). Despite this relatively quiescent and differentiated state they can dedifferentiate and switch to a proliferative phase. Such phenotypic switching was described in cell culture (Chamley et al., 1974) and is now recognized as one of the principal mechanism by which arteries respond to injuries. The response can lead to excessive VSMC proliferation and occlusion of the vascular lumen. Formation of an enlarged neointimal layer is a frequent and unwanted side-effect of diverse routine vascular surgeries, such as angioplasty, stenting and reconstructive microsurgery. In vascular stenting, restenosis manifests in cell proliferation inside the implanted stent leading to turbulent flow and eventual thrombosis, requiring stent replacement. Restenosis affected more than 30% of patients undergoing coronary stenting, but the rates have dropped to around 5% due to the development and use of drug-eluting stents that inhibit the proliferative response (Byrne et al., 2015; Cassese et al., 2014). These pharmaceutical advances have remained limited in their adoption to many other types of vascular surgeries that consequently have seen little improvement in long-term efficacy. 5-year failure rates have remained 30–50% in peripheral bypass surgery due to intimal hyperplasia (Owens et al., 2008). Understanding the cellular and molecular mechanisms that mediate arterial injury response has important implications for vascular surgery. The response of arteries to injury varies significantly in the extent of neointima formation and in their primary cell source (Yang et al., 2016). Studies using transgenic mouse models marking mature VSMCs have indicated that the majority of neointimal cells arise from medial VSMCs (Herring et al., 2014; Nemenoff et al., 2011). Intriguingly, such VSMC proliferative response is not random and involves only the activation of a minor subset of mature cells. Using multicolor clonal analysis of arterial injury response Chappell et al. found that less than 114

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Fig. 3. Arterial wall response to minor and severe vascular injury. A, Intimal injury (on the left) triggers limited inflammatory response by leukocytes and activation of adipocytes, leading to phenotypic switching of mature VSMCs and their proliferation in the neointima. Severe injury (on the right) leads to VSMC death and emergence of acellular arterial walls that are repopulated by adventitial cells giving rise to new VSMCs. The specific contribution of tunica intima resident cells to injury induced intimal hyperplasia is still largely unknown. B, Simplified schematic of VSMC phenotypic switching. PDGF-BB leads via ERK signaling to ELK1 phosphorylation. Activated ELK1 competes with MYOCD and MRTF-A/B for binding to SRF and activates the expression of cell proliferation associated genes. PDGF-BB induced transcription of SP1 triggers upregulation of KLF4 that inhibits MYOCD transcription. KLF4 however also inhibits cell proliferation by triggering p21 expression and can therefore limit the extent of intimal hyperplasia. Several other pathways add to the proliferative change and include NOTCH ligand DLL4 and diverse inflammatory cytokines.

The cellular response to injury depends on the extent of vascular wall damage. We recently compared the response of the femoral artery to minor wire-induced injury and to severe injury caused by complete transection and anastomotic repair. In limited intimal injury dedifferentiation of mature VSMCs is the primary source of neointimal cells (Roostalu et al., 2017). In contrast, severe injury that spans all arterial wall cell layers causes rapid VSMC death. Intriguingly, such acellular vascular wall retains its patency (Clarke et al., 2006). In this case mature VSMCs in neighboring arterial regions lack sufficient migratory capacity to recolonize the acellular regions and instead local proliferation and differentiation of adventitial cells leads to the recellularization of the regenerating artery (Roostalu et al., 2017). In a similar manner, in arterial allograft model adventitial cells were found to colonize the intima (Grudzinska et al., 2013). The available data suggest that arterial injury response varies depending on the mechanism of injury and this dictates the pattern of involvement of the different cell types (Fig. 3). Furthermore, even within the same artery, the response may vary depending on the distance from the site of injury or surgery, which may be associated with proximal to distal axis or direction of blood flow. In many ways arterial injury response and regeneration recapitulate embryonic developmental pathways. In the absence of resident VSMCs, endothelial derived signals are likely to recruit naïve adventitial cells to the vascular wall, followed by their smooth muscle differentiation. If the injury is however more limited, VSMC proliferation occurs similarly to their proliferation in the growth of fetal and postnatal arteries. Importantly, however, the proliferative response is poorly controlled, leading to extensive accumulation of immature VSMCs that fail to redifferentiate (Fig. 3). Among the key differences between embryonic development of arteries and their postnatal injury response lies in the involvement of several other cell types that are absent or inactive at the time of arterial development. Intimal hyperplasia is regulated by inflammatory cells and other perivascular cells. Leukocytes accumulate at the site of arterial injury and promote intimal hyperplasia (De Servi et al., 1990; Miller et al., 2001; Noma et al., 2008). Depletion of leukocytes reduced neointima formation following angioplasty

0.1% of medial VSMCs contribute to intimal hyperplasia. Most neointimal areas were composed of the progeny of a single lineage (Chappell et al., 2016). The reason why some cells are more susceptible to injury induced proliferation than others has remained unknown. In contrast to the accumulating data on the role of VSMCs in intimal hyperplasia other studies have suggested that various progenitor cells may have a major impact in arterial wall remodeling. It has been proposed that SOX10+ multipotent stem cells may be the primary progenitors to neointimal cells (Tang et al., 2012). It should however be noted that Sox10 can be expressed by VSMCs, complicating the use of this marker in fate-mapping studies in mice (Kennedy et al., 2014). The evidence for the contribution of adventitial cells is likewise contradictory. Fate mapping using Gli1-CreER transgenic mouse model revealed that a large fraction of neointimal cells arise from GLI1+ progenitors. Under healthy physiological conditions GLI1 expression is largely limited to adventitial cells, leading to the suggestion that these cells may penetrate the vascular wall in response to injury (Kramann et al., 2016). Yet, several lines of evidence suggest that mature VSMCs can also respond to Sonic Hedgehog signaling and activate GLI transcription factor dependent pathways. Sonic Hedgehog pathway mediates VSMC phenotypic switching, proliferation and enhanced expression of NOTCH target genes (Li et al., 2010; Morrow et al., 2009; Wang et al., 2010; Zeng et al., 2016). It thus remains to be proven to what extent GLI1 fate-mapping transgenic model reports the response of mature VSMCs that undergo a brief phase of GLI expression or, in contrast, migration and differentiation of adventitial progenitor cells. Contrary to these studies Shen et al. found only limited migration of CD34+ adventitial cells to the outer layers of injured arterial wall (Shen et al., 2016). Accurate estimation of the direct role of adventitial cells in arterial injury response is made even more complicated by the fact that these cells can develop from mature VSMCs and vice versa, some VSMC can arise from adventitia. Nevertheless, in addition to their direct differentiation it is also important to consider the paracrine effect of adventitial cells as they can respond to Sonic Hedgehog and PDGF-BB signaling and enhance VSMC proliferation (Dutzmann et al., 2017). 115

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dependent manner. Endothelial cells were recently found to undergo mesenchymal transition in vein grafts in response to TGFβ signaling, contributing to intimal hyperplasia. Endothelial specific deletion of Smad2 limited intimal hyperplasia in response to injury, demonstrating the significance of endothelial cells in arterial wall remodeling (Cooley et al., 2014). The role of TGFβ and the process of endothelial to mesenchymal transformation are well reported in the context of injury and several diseases (Aisagbonhi et al., 2011; Dejana et al., 2017; Pardali et al., 2017). These studied highlight the difficulties of targeting TGFβ signaling specifically in VSMCs. Similarly to its function in embryonic VSMC development NOTCH signaling has a multifaceted and dynamic role in neointima formation. On one hand NOTCH receptors, in particular NOTCH3, are downregulated in VSMCs in the first 5 days following arterial injury (Wang et al., 2002b). This transient NOTCH3 downregulation coincides with dedifferentiation of VSMCs (Keuylian et al., 2012). While these studies can suggest that NOTCH3 may limit phenotypic switching of VSMCs, inhibition of NOTCH pathway was found to have a beneficial effect in limiting intimal hyperplasia in preclinical rat balloon-induced injury model (Caolo et al., 2011). Thus the precise role of NOTCH signaling depends on the particular receptor and ligand pairs and the cells that expose these. Similarly to embryonic development, JAG1 is upregulated in regenerating endothelial cells, which trigger JAG1 expression in VSMCs. This paracrine signaling pathway limits VSMC dedifferentiation as attenuation of endothelial JAG1 enhances VSMC phenotypic switching (Wu et al., 2011). In contrast, DLL4 is upregulated in inflammatory macrophages and can increase VSMC proliferation and migration, while suppressing their differentiation (Koga et al., 2015). The above described PDGF-B, TGFβ and NOTCH pathways represent only few examples of the molecular signaling networks that control VSMC phenotypic switching in the injured arterial wall. Yet, they also demonstrate the complexities that exist in finding pharmacological targets to prevent or limit intimal hyperplasia as these and other pathways have often diverging roles in endothelial cells, VSMCs and yet poorly characterized vascular wall progenitor cells.

(Danenberg et al., 2003; Miller et al., 2001). Vascular injury triggers inflammation of the perivascular adipose tissue and accumulating evidence suggests that adipocytes may enhance and contribute to the inflammatory response by upregulating adhesion molecules, changing to a proliferative phenotype and promoting VSMC phenotypic switching by cytokine secretion (Manka et al., 2014; Moe et al., 2013; Okamoto et al., 2001; Takaoka et al., 2010; Tian et al., 2013). The molecular regulation of VSMC phenotypic switching has been extensively studied and reviewed elsewhere (Alexander and Owens, 2012; Bennett et al., 2016; Davis-Dusenbery et al., 2011b). It involves complex signaling cascades that in response to inflammatory cytokines and growth factors result in gene expression changes in VSMCs, leading to their proliferation and migration. In this review we only provide an overview of how the core growth factor dependent signaling pathways that regulate VSMC differentiation in the embryo are reactivated in the injured arterial wall and why this activation leads to excessive proliferative response. Among the best examples is the PFGF-BB pathway. Intimal hyperplasia is positively regulated by PDGF-BB and its inhibition reduces it (Caglayan et al., 2011; Davies et al., 2000; Law et al., 1996). Similarly, IGF-I is markedly upregulated in the tunica media VSMCs following arterial injury (Khorsandi et al., 1992), and its induced overexpression in VSMCs enhances intimal hyperplasia (Zhu et al., 2001), whereas abrogation of the signaling pathway inhibits neointima formation (Hayry et al., 1995). PDGF-BB and IGF-I act in arterial repair as chemoattractants (Bornfeldt et al., 1994). As such, their ectopic release can guide VSMCs away from the lumen and reduce intimal hyperplasia (Wong et al., 2001). In addition PDGF-BB directly represses the expression of VSMC contractile proteins by inducing expression KLF4 via SP1 (Stimulating Protein 1) transcription factor (Deaton et al., 2009; Liu et al., 2005). It also activates ELK1, which competes with MYOCD and MRTF-A/B, leading to diverse downstream transcriptional and epigenetic changes and enhanced cell proliferation (Yoshida et al., 2007). PDGF-BB has thus a central role in the phenotypic switching and several studies have demonstrated the efficacy of PDGFRβ inhibitor eluting stents in animal models (Bilder et al., 2003; Huang et al., 2017; Jandt et al., 2010; Masuda et al., 2011). Clinical trials have assessed the efficacy of oral dosing of Trapidil, an inhibitor of PDGF-BB signaling, to reduce intimal hyperplasia. While early limited studies indicated varying levels of efficacy (Maresta et al., 1994, 2005; Okamoto et al., 1992), large scale trials failed to confirm a significant beneficial effect (Serruys et al., 2001). It is likely that such oral delivery fails to target proliferative VSMCs efficiently for sustained periods and prolonged drug eluting stents are needed. PDGF signaling illustrates also how arterial injury response differs from arterial wall differentiation in embryonic development. Whereas endothelial cells are the primary source of PDGF in arterial development, intimal VSMCs, activated macrophages and platelets secrete PDGF following arterial injury and thereby induce disproportionate VSMC proliferation (Majesky et al., 1990; Margolin et al., 1993; Morisaki et al., 1992; Ross et al., 1990). TGFβ provides another example of how a signaling molecule that regulates VSMC embryonic differentiation can alter arterial injury response. TGFβ is secreted by activated macrophages, platelets and VSMCs (Assoian et al., 1987; Assoian and Sporn, 1986; Grainger et al., 1995; Ostriker et al., 2014). Inhibition of TGF-β signaling by systemic delivery of antibodies against TGFβ1, soluble decoy receptor, or oligonucleotides, reduces intimal hyperplasia after balloon-induced injury in animal models (Kingston et al., 2001; Wolf et al., 1994; Yamamoto et al., 2000). However, these methods did not target specifically vascular wall cells. VSMC-specific knockout of TGFβR1 led to short-term attenuation of neointima formation, but caused defective arterial wall regeneration due to impaired VSMC differentiation and extracellular matrix synthesis (Liao et al., 2016). This result underscores the importance of TGFβ pathway in controlling VSMC maturation. The contradictory results suggest that other cell types in addition to VSMCs may contribute to intimal hyperplasia in TGFβ-

7. Future directions Extensive research has identified a variety of cell types in the arterial wall. Our understanding of their specific functions in healthy vascular physiology and in the injured artery is still limited. The key challenge here is to identify more precise means to study their fate and function in vivo. Single cell sequencing can reveal novel markers that can be used to generate more specific transgenic animal models. Moreover, rapid development of CRISPR-Cas9 technology may offer even more accurate tools to track the fate of individual cells in the vascular wall in embryonic development and in models of cardiovascular diseases (McKenna et al., 2016). Intriguing fundamental questions have remained open concerning the embryonic development of arteries. While in vitro studies have provided us with detailed understanding of the signaling pathways that regulate VSMC differentiation less is known how these are orchestrated in the formation of multilayered arterial walls. How is arterial wall thickness controlled? How is the cellular morphology of arterial branching sites defined and maintained? The response of VSMCs to arterial injury largely involves the same pathways that control their proliferation in embryonic development. Yet, we still do not know how the switch to proliferative phase is regulated and why only few VSMCs appear to respond to the signals? Future studies are needed to find cytokines and other stimulatory molecules that control the switch and to determine how regulatory non-coding RNAs and epigenetic changes can be used to inhibit intimal hyperplasia. The current pharmaceutical approaches that are used in drug eluting stents to target intimal hyperplasia rely on compounds that lack specificity in inhibiting the proliferation of cell types in the vascular wall. Such drugs prevent the regeneration of the endothelial cell layer, prolong the healing process and can lead to eventual 116

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