Vascular morphogenesis: tales of two syndromes

Abstract

Advances in our understanding of fundamental biological processes can be made by the analysis of defects manifested in inherited diseases. The genes responsible for these genetic syndromes often encode proteins that act at critical points of the pathways that control biological processes such as cell proliferation, cell-cell communication, cellular differentiation, and cell death. This approach has lead to the discovery of novel gene products and/or biochemical pathways involved in disease, genes that in turn play a fundamental role in normal biological processes. This forward genetic approach, focusing on Mendelian disorders of vascular anomalies, has been particularly fruitful for the study of genetic regulation of angiogenesis. This review summarizes the ongoing saga of two genetic syndromes involving disruption of normal vascular morphogenesis. Each inherited disorder involves the focal development of a distinct vascular anomaly. In hereditary hemorrhagic telangiectasia (HHT), the hallmark vascular lesion is termed an arteriovenous malformation, which involves the direct communication of an artery with a vein (arteriovenous shunt), without an intervening capillary bed. For cerebral cavernous malformations (CCM), the lesions are grossly-dilated, closely-packed, capillary-like sinusoidal chambers. The autosomal dominant mode of inheritance of each of these distinct syndromes suggested that the underlying genes might regulate critical aspects of vascular morphogenesis. Emerging but intriguing tales are being told by the genes (and their protein products) mutated in these disorders.

Modulation of activin/bone morphogenetic protein signaling by follistatin is required for the morphogenesis of mouse molar teeth

“…The extracellular matrix was reduced, and the closely packed cells were cuboidal in shape in contrast to the wild-type loose stellate reticulum with starshaped cells. Because the stellate reticulum becomes highly vascularized during advancing tooth development (Bonnaud, 1984) and because activin A and follistatin have been implicated in the regulation of angiogenesis (Breit et al, 2000;Larsson et al, 2001;Marchuk et al, 2003), we wondered whether a lack of angiogenesis could explain the morphology of the mutant stellate reticulum and perhaps also the reduced proliferation in the enamel epithelium. Therefore, we localized blood vessels by immunohistochemistry using an antibody against the basement membrane protein laminin, which has earlier been shown to mark blood vessels in the stellate reticulum (Thesleff et al, 1981).…”

Redundant roles ofSox17andSox18in postnatal angiogenesis in mice

“…Several experimental models with defective postnatal angiogenesis show retarded and defective growth of various organs (Gerber et al, 1999;Mattot et al, 2002;Malik et al, 2006), suggesting its crucial roles in organ growth and maturation in postnatal life. Moreover, insufficient or aberrant new blood vessel formation is also known to cause the various pathological states such as edema, hemorrhage, bleeding, angiomas and ischemic necrosis (Vikkula et al, 2001;Marchuk et al, 2003;Timur et al, 2005;Boon et al, 2005).…”

Molecular and Genetic Basis of Cerebral Cavernous Malformations

“…KRIT1 geninin kaybı, SKM lezyonlarının ortaya çıkışında oldukça önemli olup; hücresel morfolojinin belirlenmesinde dinamik bir yapı sergilemektedir (16). üretilen proteinin 3 adet NPxY/F motifi ve ankirin tekrarlı bir yapıya sahip N-terminalini, 14-20 eksonları da 4.1 ezrin, radixin, moesin (FERM) domainini barındıran C-terminalini kodlamaktadır(Şekil 2A) (4,11). Bu NPxY/F motiflerinden ilki β1-integrin regülatörü olan integrin sitoplazmik adaptör proteini 1 alfa (ICAP1α) ile etkileşime girerek β1-integrine, talin ve kindlin proteinlerinin bağlanmasına engel olur.…”