Transforming Growth Factor-βs and Vascular Disorders

Abstract

Abstract-Transforming growth factor-␤ (TGF-␤) superfamily members, TGF-␤ and bone morphogenetic proteins (BMPs), are potent regulatory cytokines with diverse functions on vascular cells. They signal through heteromeric type I and II receptor complexes activating Smad-dependent and Smad-independent signals, which regulate proliferation, differentiation, and survival. They are potent regulators of vascular development and vessel remodeling and play key roles in atherosclerosis and restenosis, regulating endothelial, smooth muscle cell, macrophage, T cell, and probably vascular calcifying cell responses. In atherosclerosis, TGF-␤ regulates lesion phenotype by controlling T-cell responses and stimulating smooth muscle cells to produce collagen. It contributes to restenosis by augmenting neointimal cell proliferation and collagen accumulation. Defective TGF-␤ signaling in endothelial cells attributable to mutations in endoglin or the type I receptor ALK-1 leads to hereditary hemorrhagic telangiectasia, whereas defective BMP signaling attributable to mutations in the BMP receptor II has been associated with development of primary pulmonary hypertension. The development of mouse models with either cell type-specific or general inactivation of TGF-␤/BMP signaling has started to reveal the importance of the regulatory network of TGF-␤/BMP pathways in vivo and their significance for atherosclerosis, hereditary hemorrhagic telangiectasia, and primary pulmonary hypertension. This review highlights recent findings that have advanced our understanding of the roles of TGF-␤ superfamily members in regulating vascular cell responses and provides likely avenues for future research that may lead to novel pharmacological therapies for the treatment or prevention of vascular disorders.

MicroRNA‐216a induces endothelial senescence and inflammation via Smad3/IκBα pathway

“…Expression of TGFβ1 and receptors is increased in human atherosclerotic plaque lesion, especially in fibro‐proliferative regions, compared with non‐atherosclerotic regions 17, 18. TGFβ1 can stimulate endothelial migration, proliferation and angiogenesis at low concentrations, but inhibit these functions at higher concentrations, which associated with increased extracellular matrix 19. In this study, the TGFβ1 expression in senescent PDL44 HUVECs was significantly decreased compared with that in young PDL8 cell line.…”

Role of Macrophage Socs3 in the Pathogenesis of Aortic Dissection

“…Therefore, macrophage Socs3 seems to regulate the response of VSMCs and tissue repair through macrophage‐VSMC interaction 25. Because phenotypic modulation of VSMCs and transforming growth factor beta signaling are essential for arterial injury repair26, 27 and aortic wall homeostasis,28 aberrant responses of VSMCs and transforming growth factor beta signaling in mSocs3‐KO mice may be involved in the progression from the focal medial disruption to AD, possibly attributed to the failure of repair response. The importance of VSMCs in AD pathogenesis is underscored by the fact that mutations in the contractile proteins of VSMCs predispose patients to AD 1.…”

TGF-β signaling in vascular biology and dysfunction

“…Vascular SMCs express multiple type I and type II receptors for TGF-β family members [60]. TGF-β is a potent stimulator of vascular SMC differentiation by activating the genetic program that includes a large set of SMC differentiation marker genes [61].…”