Coronary Vessel Development Is Dependent on the Type III Transforming Growth Factor β Receptor

Abstract

Abstract-Transforming growth factor (TGF)␤ receptor III (TGF␤R3), or ␤-glycan, binds all 3 TGF␤ ligands and inhibin with high affinity but lacks the serine/threonine kinase domain found in the type I and type II receptors (TGF␤R1, TGF␤R2). TGF␤R3 facilitates signaling via TGF␤R1/TGF␤R2 but also has been suggested to play a unique and nonredundant role in TGF␤ signaling. Targeted deletion of Tgfbr3 revealed a requirement for Tgfbr3 during development of the coronary vessels. Coronary vasculogenesis is significantly impaired in null mice, with few vessels evident and numerous, persistent blood islands found throughout the epicardium. Tgfbr3-null mice die at embryonic day 14.5, the time when functional coronary vasculature is required for embryo viability. However, in null mice nascent coronary vessels attach to the aorta, form 2 coronary ostia, and initiate smooth muscle recruitment by embryonic day 14. Analysis of earlier developmental stages revealed defects in the epicardium. At embryonic day 13.5, these defects include an irregular and hypercellular epicardium with abundant subepicardial mesenchyme and a thin compact zone myocardium. Tgfbr3-null mice also displayed other defects in coronary development, including dysmorphic and distended vessels along the atrioventricular groove and subepicardial hemorrhage. In null mice, vessels throughout the yolk sac and embryo form and recruit smooth muscle in a pattern indistinguishable from heterozygous or wild-type littermates. These data demonstrate a requirement for Tgfbr3 during coronary vessel development that is essential for embryonic viability. Key Words: coronary vessels Ⅲ transforming growth factor ␤ receptor Ⅲ mice, null C oronary artery disease is responsible for 54% of all cardiovascular disease in the United States. 1 Coronary vessels have a unique derivation from mesothelial cells that form a transitory structure termed the proepicardium. Proepicardial cells are transferred to the heart, form the epicardium, and give rise to endothelial cells, smooth muscle cells, and cardiac fibroblasts (reviewed elsewhere 2,3 ). Endothelial cells derived from the epicardium form a vascular plexus by the process of vasculogenesis. This vascular network attaches to the aorta and recruits epicardially derived mesenchyme to become vascular smooth muscle. The identification of the molecular and cellular processes that regulate coronary vessel development may provide insight into coronary vessel disease and reveal novel therapeutic opportunities.The transforming growth factor (TGF)␤ family of growth factors regulates cell growth and differentiation in the cardiovascular system during both development and disease. 4 -6 Three ligands, TGF␤1, TGF␤2, and TGF␤3, 7-9 bind 4 cell surface proteins. These include two transmembrane serine/ threonine kinase receptors, the type I TGF␤ receptor (TGF␤R1) and the type II TGF␤ receptor (TGF␤R2). 10 -12 Several type I receptors, termed activin receptor-like kinases (ALKs), have been described. TGF␤R2 has a constitutively active cytoplasmic...

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

“…On the other hand, a primary defect caused by reduced TGFb signalling in the heart would be consistent with the increased frequency of VSDs seen in embryos that are non-haemorrhagic, but are deficient in betaglycan, an auxiliary receptor that promotes TGFb2 signalling (Stenvers et al, 2003;Compton et al, 2007). In one of these studies, Betaglycan null embryos died at E14, which was thought to be a result of lack of coronary vessels (Compton et al, 2007). In contrast, coronary vessel development appeared to be unaffected in the endothelial-specific Tgfbr2 knockout mice in our study (data not shown).…”

“…Alternatively, it is also formally possible that the high frequency of VSDs in these mutants may be a secondary consequence of cerebral haemorrhage leading to reduced blood flow that might, in turn, affect maturation of the heart. On the other hand, a primary defect caused by reduced TGFb signalling in the heart would be consistent with the increased frequency of VSDs seen in embryos that are non-haemorrhagic, but are deficient in betaglycan, an auxiliary receptor that promotes TGFb2 signalling (Stenvers et al, 2003;Compton et al, 2007). In one of these studies, Betaglycan null embryos died at E14, which was thought to be a result of lack of coronary vessels (Compton et al, 2007).…”

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

“…TGFβR3 mRNA is also induced by glucocorticoids, especially aldosterone, dexamethasone, and hydrocortisone, in hepatic stellate cells, fibroblasts, and osteoblasts, which suggests a critical role for TGFβR3 in controlling pleiotropic cellular effects 20. During coronary vessel development, TGFβR3 is dynamically regulated and is required; TGFβR3‐null mice cannot survive after embryonic day 14.5 21. In addition, β‐arrestin2 promotes the endocytosis of TGFβR3, and TGFβR3 and β‐arrestin2 coordinately function to regulate epithelial and cancer cell migration 22.…”

Co-ordinating Notch, BMP, and TGF-β signaling during heart valve development

“…Deletion of either of the TGFβ co-receptors, Endoglin and Betaglycan, results in embryonic lethality due to cardiac defects [97][98][99][100]. Endoglin −/− embryos die at E11 with enlarged ventricles, dilated OFT, cardiac cushions that lack mesenchyme cells, and angiogenic defects in yolk sac; whereas, Betaglycan null mice are embryonic lethal at E14.5 due to coronary vascular developmental defects such as hypercellular epicardium, dysmorphic vessels at the AV groove and subepicardial haemorrhage [97][98][99][100].…”

“…Endoglin −/− embryos die at E11 with enlarged ventricles, dilated OFT, cardiac cushions that lack mesenchyme cells, and angiogenic defects in yolk sac; whereas, Betaglycan null mice are embryonic lethal at E14.5 due to coronary vascular developmental defects such as hypercellular epicardium, dysmorphic vessels at the AV groove and subepicardial haemorrhage [97][98][99][100]. Betaglycan null mice also have defects in septation, OFT alignment, and myocardial thinning, although these defects are likely not the cause of lethality [100].…”