Vascular morphogenesis: tales of two syndromes.
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.
Marchuk
Douglas A
DA
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Box 3175, Durham, NC 27710, USA. march004@mc.duke.edu
Srinivasan
Sudha
S
Squire
Teresa L
TL
Zawistowski
Jon S
JS
D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II; D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD; D001808:Blood Vessels / Q000473:pathology / Q000502:physiology*; D001927:Brain Diseases / Q000473:pathology; D002448:Cell Adhesion; D002450:Cell Communication; D002455:Cell Division; D003599:Cytoskeleton / Q000378:metabolism; D000071063:Endoglin; D005799:Genes, Dominant; D006801:Humans; D016023:Integrins / Q000378:metabolism; D000075927:KRIT1 Protein; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D013577:Syndrome; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D016023:Integrins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; C491535:Krit1 protein, mouse; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse