TGF-β Signaling in Control of Cardiovascular Function

Abstract

Genetic studies in animals and humans indicate that gene mutations that functionally perturb transforming growth factor b (TGF-b) signaling are linked to specific hereditary vascular syndromes, including Osler-Rendu-Weber disease or hereditary hemorrhagic telangiectasia and Marfan syndrome.Disturbed TGF-b signaling can also cause nonhereditary disorders like atherosclerosis and cardiac fibrosis.Accordingly, cell culture studies using endothelial cells or smooth muscle cells (SMCs), cultured alone or together in two-or three-dimensional cell culture assays, on plastic or embedded in matrix, have shown that TGF-b has a pivotal effect on endothelial and SMC proliferation, differentiation, migration, tube formation, and sprouting.Moreover, TGF-b can stimulate endothelial-to-mesenchymal transition, a process shown to be of key importance in heart valve cushion formation and in various pathological vascular processes.Here, we discuss the roles of TGF-b in vasculogenesis, angiogenesis, and lymphangiogenesis and the deregulation of TGF-b signaling in cardiovascular diseases.T ransforming growth factor b1 (TGF-b1) is the prototype of a large family of structurally related, secreted dimeric proteins that have pleiotropic effects and play important roles in cell-to-cell signaling.Other members of this family include the closely related TGF-b2 and -b3 and more distantly related proteins like activins and inhibins, nodal proteins, and bone morphogenetic proteins (BMPs) (Hinck et al. 2016;Morikawa et al. 2016).TGF-bs regulate a large variety of cellular processes in many different cell types.Their effects are context-dependent, including the induction of proliferation, apoptosis, migration, adhesion, extracellular matrix (ECM) protein production, and cytoskeletal organization (Massague ´2012; Mori-kawa et al. 2016).Consequently, many TGF-b family cytokines play essential roles in embryonic development, stem cells, and cell fate determination and in adult tissue homeostasis and repair (Moustakas and Heldin 2009;Wu and Hill 2009;Itoh et al. 2014).Perturbations in the actions of TGF-b can lead to pathological conditions, including cardiovascular diseases, fibrotic disorders, and cancer (Harradine and Akhurst 2006; Ikushima and Miyazono 2010; Dooley and ten Dijke 2012; Pardali and ten Dijke 2012; Morikawa et al. 2016).Therapeutic intervention to normalize perturbed TGF-b signaling is an emerging area of intense research (Hawinkels and ten Dijke 2011; Akhurst and