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Pericytes may have an important role in the pathogenesis of vascular malformations
Medical Hypotheses (2007) 68, 808–810
http://intl.elsevierhealth.com/journals/mehy
Pericytes may have an important role in the pathogenesis of vascular malformations Chen Li a, Wen-Feng Zhang a, Yi-Fang Zhao
a,b,*
a
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan 430079, PR China b Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan, PR China Received 26 August 2006; accepted 6 September 2006
Summary Vascular malformations are a series of congenital developmental abnormalities. The defects in vascular remodeling may contribute to the formation of these unique entities. Pericytes are the component of microvascular system and play a key role in vascular remodeling. It is logical to propose pericytes may play an important role in the pathogenesis of vascular malformations. Target therapies against pericytes probably bring new sight into vascular malformations treatment. c 2006 Elsevier Ltd. All rights reserved.
Introduction Vascular malformations are a series of congenital developmental abnormalities of vascular system. They are commonly found in children. The lesions are always present at birth and grow commensurately with the growth of the patients. Unlike hemangioma, vascular malformations never proliferate nor do involute, but expand relentless throughout the patient’s life. Vascular malformations are mainly composed of unorganized and distorted enlarged vascular channels with quiescent lining endothelial cells in lesions of all ages [1]. Although * Corresponding author. Address: Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan 430079, PR China. Tel.: +86 27 87647434; fax: +86 27 87873260. E-mail address: [email protected] (Y.-F. Zhao).
several gene mutations had been identified in hereditary vascular malformations, the etiology of sporadic vascular malformations still need further investigation [2,3]. Brouillard et al. [4] proposed the concept that vascular malformations were the defects of vascular remodeling of the primary capillaries plexus in vascular development. Arteriovenous malformation models also reflect a vascular remodeling disruption [5]. Vascular remodeling is the following step of angiogenesis during vascular development [6]. This process includes the connection of vessels with different sizes, the directional blood flow establishment, mural cells (pericytes and smooth muscle cells) recruitment and interaction with endothelial cells, and the regression of unnecessary vessels base on the nutritional and hypoxia requirement of adjacent tissues. Although both smooth muscle cells and pericytes can co-exist during vascular
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.09.010
Pericytes may have an important role in the pathogenesis of vascular malformations development, the pericytes may be the smooth muscle cells’ precursor in vessel elongation and remodeling [7]. The pericytes differentiate from the undifferentiated mesenchymal cells and recruited to the endothelial tubes to form gap-junction with endothelial cells. This process mainly be mediated by platelet-derived growth factor b (PDGF-b) [8] and transforming growth factor b (TGF-b) [9] secreted by endothelial cells in paracrine pathway. Pericytes coverage of vessels marks the end of remodeling process and maturation of vascular system [10]. Previous studies have suggested that the both the accurate location of pericytes and endothelial-pericytes interactions are critical for proper vascular development and maintenance of integrity [11]. Pericytes-derived vascular endothelial growth factor (VEGF) had been known as the strongest angiogenic growth factors associated with endothelial cells survival and stability [12]. Angiopoitin-1, the soluble factors synthesized and secreted by pericytes may increase occludin expression in regulating vascular permeability. Deficiency in Angiopoitin-1 or its receptor Tie-2 may perturb vascular development and contribute to embryonic lethality [13]. Therefore, mutation of the two factors was observed in familial venous malformation [14]. One major role of pericytes is to maintain a uniform capillary diameter through contractile ability. Lack of pericytes or disruption of endothelial-pericytes association also contributes to abnormal vascular morphogenesis and functions. Absence of pericytes may lead to local dilation of vessel diameter with severe differences and microaneurysm formation [15]. These phenomena may result from loss of structural support of pericytes under blood pressure [16]. Reduced pericytes number or dysfunction was observed in many pathological processes. Pericyte loss, microaneurysms are early characteristics of diabetic retinopathy. Pericytes deficiency may lead to increased endothelial cells proliferation and irregularities of the microvascular system [17]. Reduced extension of pericytic investment displayed in peritumoral brain tissues was coincided with edema of nerve tissues [18]. Angiogenic pericytes marker, G-protein signaling-5 (RGS-5) transcriptive level up-regulation in astrocytomas indicated the phenotype change of pericytes in the dilated and tortuous tumor vessels [19].
The hypothesis Recent advances in exploration of vascular remodeling bring new understanding in the pathogenesis of vascular malformations. Pericytes as the important
809
component of microvascular system play a crucial role in vascular remodeling and maturation. The disruption of endothelial-pericytes interactions in vascular remodeling may lead to defective vascular morphogenesis and functions. Although no specific role of pericytes had been reported in vascular malformations, the close relationship of vascular malformations and defective vascular remodeling indicated the potential functions of pericytes in the pathogenesis of these unique entities. We suggest that decreased or deficient pericytes may contribute to the pathogenesis of vascular malformations. Regulation of endothelial-pericytes association may intervene the natural history and induce involution of these developmental abnormalities.
Implication of the hypothesis To further investigate the role of pericytes in vascular malformations will lead to a new sight in the pathogenesis of these developmental anomalies. The structural differences between the vessels in normal tissues and vascular malformations provide the possibility for target therapy against the abnormal vessels in the lesion. Target therapy against pericytes, which differentiation and proliferation are induced by intralesional application of soluble factors or agents, possibly reverses abnormal vasculature to a normal morphology. Combinatorial targeting of signal pathways involving in endothelial-pericytes interactions may also have good effects [20].
References [1] Waner M, Suen JY. Hemangiomas and vascular malformations of the head and neck. New York: Wiley-Liss Inc.; 1999. P.93–149. [2] Eerola I, Boon LM, Watanabe S, et al. Locus for susceptibility for familial capillary malformation (‘port-wine stain’) maps to 5q. Eur J Hum Genet 2002;10:375–80. [3] Vikkula M, Boon LM, Carraway III KL, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996;87:1181–90. [4] Brouillard P, Vikkula M. Vascular malformations: Localized defects in vascular morphogenesis. Clin Genet 2003;63: 340–51. [5] Wakhloo AK, Lieber BB, Siekmann R, et al. Acute and chronic swine rete arteriovenous malformation models: Hemodynamics and vascular remodeling. AJNR Am J Neuroradiol 2005;26:1702–6. [6] August P, Suthanthiran M. Transforming growth factor beta signaling, vascular remodeling, and hypertension. N Engl J Med 2006;354:2721–3. [7] D’Amore PA. Capillary growth: A two-cell system. Semin Cancer Biol 1997;3:49–56. [8] Hellstrom M, Kalen M, Lindahl P, et al. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells
810
[9]
[10]
[11] [12]
[13]
[14]
Li et al. and pericytes during embryonic blood vessel formation in the mouse. Development 1999;126:3047–55. Shih SC, Ju M, Liu N, et al. Transforming growth factor b1 induction of vascular endothelial growth factor receptor 1: Mechanism of pericyte-induced vascular survival in vivo. Proc Natl Acad Sci USA 2003;100:15859–64. Benjamin LE, Golijanin D, Itin A, et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999;103:159–65. Folkman J, D’Amore PA. Blood vessel formation: What is its molecular basis? Cell 1996;87:1153–5. Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 2001;15:1239–41. Suri C, Jones PF, Patan S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996;87:1171–80. Vikkula M, Boon LM, Carraway KL, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996;87:1181–90.
[15] Hellstrom M, Gerhardt H, Kalen M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001;153:543–53. [16] Brands MW, Granger JP. Control of renal function and blood pressure by angiotensin II: Implications for diabetic glomerular injury. Miner Electrolyte Metab 1998;24:371–80. [17] Hammes HP, Lin JH, Renner O, et al. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002;51: 3107–12. [18] Bertossi M, Virgintino D, Maiorano E, et al. Ultrastructural and morphometric investigation of human brain capillaries in normal and peritumoral tissues. Ultrastruct Pathol 1997;21:41–9. [19] Berger M, Bergers G, Arnold B, et al. Regulator of Gprotein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood 2005;105:1094–101. [20] Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004;18:338–40.
http://intl.elsevierhealth.com/journals/mehy
Pericytes may have an important role in the pathogenesis of vascular malformations Chen Li a, Wen-Feng Zhang a, Yi-Fang Zhao
a,b,*
a
Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan 430079, PR China b Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan, PR China Received 26 August 2006; accepted 6 September 2006
Summary Vascular malformations are a series of congenital developmental abnormalities. The defects in vascular remodeling may contribute to the formation of these unique entities. Pericytes are the component of microvascular system and play a key role in vascular remodeling. It is logical to propose pericytes may play an important role in the pathogenesis of vascular malformations. Target therapies against pericytes probably bring new sight into vascular malformations treatment. c 2006 Elsevier Ltd. All rights reserved.
Introduction Vascular malformations are a series of congenital developmental abnormalities of vascular system. They are commonly found in children. The lesions are always present at birth and grow commensurately with the growth of the patients. Unlike hemangioma, vascular malformations never proliferate nor do involute, but expand relentless throughout the patient’s life. Vascular malformations are mainly composed of unorganized and distorted enlarged vascular channels with quiescent lining endothelial cells in lesions of all ages [1]. Although * Corresponding author. Address: Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan 430079, PR China. Tel.: +86 27 87647434; fax: +86 27 87873260. E-mail address: [email protected] (Y.-F. Zhao).
several gene mutations had been identified in hereditary vascular malformations, the etiology of sporadic vascular malformations still need further investigation [2,3]. Brouillard et al. [4] proposed the concept that vascular malformations were the defects of vascular remodeling of the primary capillaries plexus in vascular development. Arteriovenous malformation models also reflect a vascular remodeling disruption [5]. Vascular remodeling is the following step of angiogenesis during vascular development [6]. This process includes the connection of vessels with different sizes, the directional blood flow establishment, mural cells (pericytes and smooth muscle cells) recruitment and interaction with endothelial cells, and the regression of unnecessary vessels base on the nutritional and hypoxia requirement of adjacent tissues. Although both smooth muscle cells and pericytes can co-exist during vascular
0306-9877/$ - see front matter c 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2006.09.010
Pericytes may have an important role in the pathogenesis of vascular malformations development, the pericytes may be the smooth muscle cells’ precursor in vessel elongation and remodeling [7]. The pericytes differentiate from the undifferentiated mesenchymal cells and recruited to the endothelial tubes to form gap-junction with endothelial cells. This process mainly be mediated by platelet-derived growth factor b (PDGF-b) [8] and transforming growth factor b (TGF-b) [9] secreted by endothelial cells in paracrine pathway. Pericytes coverage of vessels marks the end of remodeling process and maturation of vascular system [10]. Previous studies have suggested that the both the accurate location of pericytes and endothelial-pericytes interactions are critical for proper vascular development and maintenance of integrity [11]. Pericytes-derived vascular endothelial growth factor (VEGF) had been known as the strongest angiogenic growth factors associated with endothelial cells survival and stability [12]. Angiopoitin-1, the soluble factors synthesized and secreted by pericytes may increase occludin expression in regulating vascular permeability. Deficiency in Angiopoitin-1 or its receptor Tie-2 may perturb vascular development and contribute to embryonic lethality [13]. Therefore, mutation of the two factors was observed in familial venous malformation [14]. One major role of pericytes is to maintain a uniform capillary diameter through contractile ability. Lack of pericytes or disruption of endothelial-pericytes association also contributes to abnormal vascular morphogenesis and functions. Absence of pericytes may lead to local dilation of vessel diameter with severe differences and microaneurysm formation [15]. These phenomena may result from loss of structural support of pericytes under blood pressure [16]. Reduced pericytes number or dysfunction was observed in many pathological processes. Pericyte loss, microaneurysms are early characteristics of diabetic retinopathy. Pericytes deficiency may lead to increased endothelial cells proliferation and irregularities of the microvascular system [17]. Reduced extension of pericytic investment displayed in peritumoral brain tissues was coincided with edema of nerve tissues [18]. Angiogenic pericytes marker, G-protein signaling-5 (RGS-5) transcriptive level up-regulation in astrocytomas indicated the phenotype change of pericytes in the dilated and tortuous tumor vessels [19].
The hypothesis Recent advances in exploration of vascular remodeling bring new understanding in the pathogenesis of vascular malformations. Pericytes as the important
809
component of microvascular system play a crucial role in vascular remodeling and maturation. The disruption of endothelial-pericytes interactions in vascular remodeling may lead to defective vascular morphogenesis and functions. Although no specific role of pericytes had been reported in vascular malformations, the close relationship of vascular malformations and defective vascular remodeling indicated the potential functions of pericytes in the pathogenesis of these unique entities. We suggest that decreased or deficient pericytes may contribute to the pathogenesis of vascular malformations. Regulation of endothelial-pericytes association may intervene the natural history and induce involution of these developmental abnormalities.
Implication of the hypothesis To further investigate the role of pericytes in vascular malformations will lead to a new sight in the pathogenesis of these developmental anomalies. The structural differences between the vessels in normal tissues and vascular malformations provide the possibility for target therapy against the abnormal vessels in the lesion. Target therapy against pericytes, which differentiation and proliferation are induced by intralesional application of soluble factors or agents, possibly reverses abnormal vasculature to a normal morphology. Combinatorial targeting of signal pathways involving in endothelial-pericytes interactions may also have good effects [20].
References [1] Waner M, Suen JY. Hemangiomas and vascular malformations of the head and neck. New York: Wiley-Liss Inc.; 1999. P.93–149. [2] Eerola I, Boon LM, Watanabe S, et al. Locus for susceptibility for familial capillary malformation (‘port-wine stain’) maps to 5q. Eur J Hum Genet 2002;10:375–80. [3] Vikkula M, Boon LM, Carraway III KL, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996;87:1181–90. [4] Brouillard P, Vikkula M. Vascular malformations: Localized defects in vascular morphogenesis. Clin Genet 2003;63: 340–51. [5] Wakhloo AK, Lieber BB, Siekmann R, et al. Acute and chronic swine rete arteriovenous malformation models: Hemodynamics and vascular remodeling. AJNR Am J Neuroradiol 2005;26:1702–6. [6] August P, Suthanthiran M. Transforming growth factor beta signaling, vascular remodeling, and hypertension. N Engl J Med 2006;354:2721–3. [7] D’Amore PA. Capillary growth: A two-cell system. Semin Cancer Biol 1997;3:49–56. [8] Hellstrom M, Kalen M, Lindahl P, et al. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells
810
[9]
[10]
[11] [12]
[13]
[14]
Li et al. and pericytes during embryonic blood vessel formation in the mouse. Development 1999;126:3047–55. Shih SC, Ju M, Liu N, et al. Transforming growth factor b1 induction of vascular endothelial growth factor receptor 1: Mechanism of pericyte-induced vascular survival in vivo. Proc Natl Acad Sci USA 2003;100:15859–64. Benjamin LE, Golijanin D, Itin A, et al. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999;103:159–65. Folkman J, D’Amore PA. Blood vessel formation: What is its molecular basis? Cell 1996;87:1153–5. Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 2001;15:1239–41. Suri C, Jones PF, Patan S, et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 1996;87:1171–80. Vikkula M, Boon LM, Carraway KL, et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 1996;87:1181–90.
[15] Hellstrom M, Gerhardt H, Kalen M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001;153:543–53. [16] Brands MW, Granger JP. Control of renal function and blood pressure by angiotensin II: Implications for diabetic glomerular injury. Miner Electrolyte Metab 1998;24:371–80. [17] Hammes HP, Lin JH, Renner O, et al. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002;51: 3107–12. [18] Bertossi M, Virgintino D, Maiorano E, et al. Ultrastructural and morphometric investigation of human brain capillaries in normal and peritumoral tissues. Ultrastruct Pathol 1997;21:41–9. [19] Berger M, Bergers G, Arnold B, et al. Regulator of Gprotein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood 2005;105:1094–101. [20] Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004;18:338–40.