Abstract
Numerous in vitro and in vivo studies implicate transforming growth factor-β (TGFβ) superfamily signaling in vascular development and maintenance. Mice and humans with mutations in TGFβ 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 TGFβ 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 TGFβ superfamily signaling during angiogenesis, we have misexpressed Smad7, an intracellular antagonist of TGFβ 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 TGFβ 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 TGFβ superfamily signaling.
Original language | English |
---|---|
Pages (from-to) | 499-516 |
Number of pages | 17 |
Journal | Developmental Biology |
Volume | 240 |
Issue number | 2 |
DOIs | |
Publication status | Published - 15 Dec 2001 |
Keywords
- TGF beta signaling
- Smad7
- arterio-venous malformation
- vascular smooth muscle
- endothelial cell
- artery
- vein
- vessel caliber
- angiogenesis
- vasculogenesis
- vasculature
- BLOOD-VESSEL FORMATION
- TRANSFORMING GROWTH FACTOR-BETA-1
- MORPHOGENETIC PROTEIN RECEPTORS
- APICAL ECTODERMAL RIDGE
- BETA FAMILY MEMBERS
- MAD-RELATED PROTEIN
- TGF-BETA
- ARTERIOVENOUS-MALFORMATIONS
- DIFFERENTIAL EXPRESSION
- INVITRO ANGIOGENESIS