Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

摘要: Vascular development depends on transforming growth factor β (TGFβ), but whether signalling of this protein is required for the endothelial cells (ECs), vascular smooth muscle (VSMCs) or both unclear. To address this, we selectively deleted type I (ALK5, TGFBR1) and II (TβRII, TGFBR2) receptors in mice. Absence either receptor ECs resulted defects yolk sac, as seen mice lacking all cells, causing embryonic lethality at day (E)10.5. Deletion TβRII specifically VSMCs also sac; however, these were observed later stages development, allowing embryo to survive E12.5. Because TGFβ can signal via ALK1 (ACVRL1), replaced ALK5 by a mutant defective SMAD2 SMAD3 (SMAD2/3) activation that retained ability transactivate ALK1. This again caused sac vasculature with E10.5, demonstrating TGFβ/ALK1 cannot compensate lack TGFβ/ALK5-induced SMAD2/3 vivo. Unexpectedly, phosphorylation α-smooth actin (SMAα, ACTA2) expression occurred sacs ALK5–/– embryos stem undergoing vasculogenesis, processes could be blocked an ALK4 (ACVR1B)/ALK5 inhibitor. Together, data show vasculogenesis; absence ALK5, mediates consequently SMAα expression.