Smad7 misexpression during embryonic angiogenesis causes vascular dilation and malformations independently of vascular smooth muscle cell function.
Numerous in vitro and in vivo studies implicate transforming growth factor-beta (TGFbeta) superfamily signaling in vascular development and maintenance. Mice and humans with mutations in TGFbeta superfamily signaling pathway genes exhibit a range of vascular defects that include dilated, fragile and hemorrhagic vessels, defective angiogenic remodeling, severe vascular malformations including arterio-venous malformations, and disrupted vascular smooth muscle cell recruitment and maintenance. Despite a wealth of data, the functions of TGFbeta superfamily signals during angiogenesis are poorly defined, since early embryonic lethality and difficulty distinguishing between primary and secondary defects frequently confound phenotypic interpretation. To perturb TGFbeta superfamily signaling during angiogenesis, we have misexpressed Smad7, an intracellular antagonist of TGFbeta superfamily signaling, in the developing chick limb and head. We find that the great vessels are strikingly dilated and frequently develop intra and intervascular shunts. Neither noggin nor dominant negative BMP receptor misexpression causes similar vascular phenotypes. However, simultaneous misexpression of constitutively active BMP receptors with Smad7 suppresses the Smad7-induced phenotype, suggesting that a BMP-like intracellular pathway is the target of Smad7 action. Despite the gross morphological defects, further analyses find no evidence of hemorrhage and vessel structure is normal. Furthermore, enlarged vessels and vascular malformations form in either the presence or absence of vascular smooth muscle, and vascular smooth muscle cell recruitment is unperturbed. Our data define the TGFbeta superfamily pathway as an integral regulator of vessel caliber that is also essential for appropriate vessel connectivity. They demonstrate that dilation need not result in vessel rupture or hemorrhage, and dissociate vessel maintenance from the presence of a vascular smooth muscle cell coat. Furthermore they uncouple vascular smooth muscle cell recruitment and differentiation from TGFbeta superfamily signaling.
Vargesson
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Department of Genetics and Development, College of Physicians and Surgeons, New York, New York 10032, USA.
Laufer
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E
D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology; D001921:Brain / Q000098:blood supply / Q000196:embryology; D002454:Cell Differentiation; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004730:Endothelium, Vascular / Q000196:embryology; D005121:Extremities / Q000098:blood supply / Q000196:embryology; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008854:Microscopy, Electron; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000196:embryology / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010641:Phenotype; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D004268:DNA-Binding Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta