24 The TGF-β Family in Endothelial Cell Differentiation and Cardiovascular Development and Function

Genetic studies in model organisms and humans have revealed pivotal roles for transforming growth factor-β (TGF-β) family members in cardiovascular development and maintenance. In vitro studies demonstrate that some TGF-β family members, signaling via their type I and type II receptors (Chapter 6) and intracellular Smads (Chapter 9), potently regulate the proliferation, differentiation, and migration of endothelial cells that line the entire vasculature and mural cells (vascular smooth muscle cells and pericytes) that surround the endothelial cells and aid in processes such as contraction. However, the context-dependent activities of TGF-β family members and their interactions with many cell types other than vascular cells, for example, epithelial and immune cells, have made the in vivo interpretation of the roles of TGF-β family members in vascular biology difficult. Here, we review the roles of TGF-β family members in cardiovascular development and function, and we discuss a model in which TGF-β signals via two distinct type I receptors in vascular cells. These receptors are the broadly expressed TGF-β type I receptor (TβRI, also termed ALK-5) acting via Smad2 and Smad3, and, the endothelial cell-restricted ALK-1 acting via Smad1 and Smad5. The roles of TGF-β family receptors in the development of hereditary hemorrhagic telangiectasia (HHT), primary pulmonary hypertension, and Marfan and Loeys-Dietz syndromes are also discussed. CARDIOVASCULAR DEVELOPMENT Vasculogenesis and Angiogenesis The first functional organ system to form in the embryo is the cardiovascular system. Shortly after gastrulation, when cells from the epiblast invaginate to become mesoderm, a vascular plexus develops in the visceral...