The discovery that mutations in the genes encoding two endothelium-restricted transforming growth factor (TGF)-β receptors – endoglin (1) and activin-like kinase 1 (ALK1) (2) – account for most, if not all cases of the human vascular disorder hereditary hemorrhagic telangiectasia (HHT) (3) firmly established the significance of direct TGF-β signaling in endothelial cells (ECs) and in vascular development. Indeed, embryonically lethal vascular phenotypes result from homozygous deletions in no less than eight components of the TGF-β signaling system, namely TGF-β1 (4), ALK1 (5), endoglin (6), ALK5(7), TGF-β receptor II (TβRII) (8), Smad5 (9), TGF-β–activated kinase (TAK)-1 (10), and furin (11) (Table 35-2). TGF-βs are key regulators of three-dimensional blood vessel structure, site-specific EC differentiation, and interactions between ECs and their immediate microenvironments. TGF-β and other superfamily members, influence ECs through direct activation and through stimuli that result in the release of endothelium-directed mediators from neighboring cells. Moreover, TGF-β–elicited EC-derived signals stimulate recruitment and differentiation of pericytes and vascular smooth muscle cells (VSMCs). TGF-β pathway activation is necessary for endothelial–mesenchymal transdifferentiation during formation of the cardiac cushion and, consequently, the cardiac valves. TGF-β derived from ECs regulates the phenotype of surrounding VSMCs.

More than 40 members of the TGF-β superfamily (12), which includes TGF-β1, TGF-β2, TGF-β–activated kinase (TAK)-1 and TGF-β3, activins, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), inhibin, and muellerian inhibitory substance (MIS), have been identified so far. Pathways for TGF-βs, BMPs, and activins, all known to stimulate ECs, are shown in Table 35–1.