ABSTRACT
Blood vessel formation is a multi-step process. Endoglin is a TGFbeta coreceptor required for angiogenesis. Endoglin null embryos exhibit a loss of arteriovenous identity and defective vascular smooth muscle cell (vSMC) recruitment. Haploinsufficiency of endoglin results in Hereditary Hemorrhagic Telangiectasia (HHT), characterized by a loss of arteriovenous identity and aberrant vSMC incorporation in fragile vessels. We explored a cell-autonomous role for endoglin in endothelial and vSMCs during angiogenesis by conditionally activating endoglin expression in wild type or endoglin null embryos using either smooth muscle (SM22alphacre) or endothelial cell (Tie2cre) promoters to partially rescue vSMC recruitment to the dorsal aorta. Examination of endoglin null embryos revealed ectopic arterial expression of the venous-specific marker COUPTFII. Endoglin re-expression in endothelial cells restored normal COUPTFII expression. These results suggested that endoglin plays distinct and cell-autonomous roles in vSMC recruitment and arteriovenous specification via COUPTFII in angiogenesis that may contribute to HHT.
Subject(s)
Arteries , COUP Transcription Factor II/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle/metabolism , Neovascularization, Physiologic , Veins , Animals , Arteries/growth & development , Arteries/metabolism , COUP Transcription Factor II/genetics , Embryo, Mammalian/anatomy & histology , Embryo, Mammalian/metabolism , Endoglin , Endothelial Cells/cytology , Endothelial Cells/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Morphogenesis/physiology , Muscle Proteins/genetics , Muscle Proteins/metabolism , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/cytology , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, TIE-2 , Telangiectasia, Hereditary Hemorrhagic/genetics , Telangiectasia, Hereditary Hemorrhagic/metabolism , Veins/growth & development , Veins/metabolism , von Willebrand Factor/genetics , von Willebrand Factor/metabolismABSTRACT
Genetic studies show that TGFbeta signaling is essential for vascular development, although the mechanism through which this pathway operates is incompletely understood. Here we demonstrate that the TGFbeta auxiliary coreceptor endoglin (eng, CD105) is expressed in a subset of neural crest stem cells (NCSCs) in vivo and is required for their myogenic differentiation. Overexpression of endoglin in the neural crest caused pericardial hemorrhaging, correlating with altered vascular smooth muscle cell investment in the walls of major vessels and upregulation of smooth muscle alpha-actin protein levels. Clonogenic differentiation assay of NCSCs derived from neural tube explants demonstrated that only NCSC expressing high levels of endoglin (NCSC(CD105+)) had myogenic differentiation potential. Furthermore, myogenic potential was deficient in NCSCs obtained from endoglin null embryos. Expression of endoglin in NCSCs declined with age, coinciding with a reduction in both smooth muscle differentiation potential and TGFbeta1 responsiveness. These findings demonstrate a cell autonomous role for endoglin in smooth muscle cell specification contributing to vascular integrity.
