TGF-β signaling in vascular biology and dysfunction

Abstract

Transforming growth factor (TGF)-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our understanding of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

“…Although VEGFR signaling could promote EC migration through mitogen‐activated protein kinase and ERK, recent studies have highlighted the role of EndMT in tip cell differentiation and migration 6, 7, 44. TGF‐β signaling is the major pathway promoting EndMT 5, 11, 12. Although endoglin functions as a coreceptor of TGF‐β signaling, this molecule has been shown to inhibit some pathways downstream from TGF‐β receptors 20, 21.…”

“…Deficiency of RBPJ, the integrative downstream transcription factor of canonical Notch signaling, leads to excessive sprouting and malformation of vessels, whereas activation of Notch signaling restricts angiogenesis 9, 10. The transforming growth factor β (TGF‐β) family of pleiotrophic cytokines, including 3 isoforms of TGF‐β, activins, and bone morphogenetic proteins elicits their biological functions through 5 type 2 receptors, 7 type 1 receptors (also termed activin receptor‐like kinases [ALKs]), and auxiliary receptors endoglin and betaglycan 11. On ligand binding, TGF‐β type 2 receptors phosphorylate type 1 receptors on specific serine and threonine residues in the intracellular domain, leading to the recruitment and phosphorylation of receptor‐regulated Smads, which associate with Smad4 to regulate the transcription of specific target genes.…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…The importance of TGF-b signaling regulation in the complex relationship between ECM and vascular cells is highlighted by the number of vascular disorders that result from failed ECMdependent regulation of TGF-b signaling or from mutations in critical mediators of TGF-b signal transduction (reviewed in Goumans and Mummery 2000; Goumans et al 2009). Of particular importance to the focus of this review are the effects of altered TGF-b signaling on the development of aneurysm, a pathological dilation of a blood vessel that can result in fatal tear and rupture.…”

“…Prenatally, TGFb and BMP signaling are key regulators of both development and morphogenesis of the vascular system (Goumans and Mummery 2000;Goumans et al 2009). Early during embryonic development, TGF-b signaling is required for formation of the vascular plexus and differentiation of both endothelial cells and VSMCs (Dickson et al 1995;Oshima et al 1996; Goumans and Mummery 2000; Larsson et al 2001;Carvalho et al 2007;Goumans et al 2009). TGF-b signaling is also required for morphogenesis of the cardiac outflow tract and VSMC-dependent deposition of elastic fibers (Wurdak et al 2005;Choudhary et al 2006).…”

Salvia Miltiorrhiza Bge.f.alba Ameliorates the Progression of Monocrotaline-Induced Pulmonary Hypertension by Protecting Endothelial Injury in Rats

“…TGF-β 1 is a multifunctional cytokine that may participate in body repair, angiogenesis, inflammation and other pathological processes, such as modulating the synthesis and secretion of other cytokines, growth factors, and inflammatory mediators (Goumans et al 2009). TGF-β 1 also plays an important role in vascular remodeling.…”