Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press TGF-b Signaling in Control of Cardiovascular Function Marie-Jose´Goumans and Peter ten Dijke Department of Molecular Cell Biology and Cancer Genomics Centre Netherlands, Leiden University Medical Center, 2300 RC Leiden, The Netherlands Correspondence: [email protected] 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 telangiecta- sia 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. ransforming growth factor b1 (TGF-b1) is kawa et al. 2016). Consequently, many TGF-b Tthe prototype of a large family of structurally family cytokines play essential roles in embry- related, secreted dimeric proteins that have onic development, stem cells, and cell fate deter- pleiotropic effects and play important roles in mination and in adult tissue homeostasis and cell-to-cell signaling. Other members of this repair (Moustakas and Heldin 2009; Wu and family include the closely related TGF-b2 and Hill 2009; Itoh et al. 2014). Perturbations in -b3 and more distantly related proteins like ac- the actions of TGF-b can lead to pathological tivins and inhibins, nodal proteins, and bone conditions, including cardiovascular diseases, morphogenetic proteins (BMPs) (Hinck et al. fibrotic disorders, and cancer (Harradine and 2016; Morikawa et al. 2016). TGF-bs regulate a Akhurst 2006; Ikushima and Miyazono 2010; large variety of cellular processes in many differ- Dooley and ten Dijke 2012; Pardali and ten Dijke ent cell types. Their effects are context-depen- 2012; Morikawa et al. 2016). Therapeutic inter- dent, including the induction of proliferation, vention to normalize perturbed TGF-b signal- apoptosis, migration, adhesion, extracellular ing is an emerging area of intense research (Ha- matrix (ECM) protein production, and cyto- winkels and ten Dijke 2011; Akhurst and Hata skeletal organization (Massague´ 2012; Mori- 2012; Chang 2016). Editors: Rik Derynck and Kohei Miyazono Additional Perspectives on The Biology of the TGF-b Family available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a022210 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press M.-J. Goumans and P. ten Dijke Misregulated TGF-b signaling in humans This vascular network is constructed using causes vascular pathologies and cardiovascular two highly coordinated and sequential process- disease such as arteriovenous malformations es,vasculogenesis and angiogenesis. During vas- (AVMs), aneurysms, atherosclerosis, cardiac fi- culogenesis (Fig. 1), mesoderm will first differ- brosis, vascular remodeling of the retina (reti- entiate into proliferating EC precursors known nopathy), and valvular heart disease. Addition- as angioblasts. These angioblasts will differenti- ally, TGF-b signaling contributes to endothelial ate into ECs that align, fuse, and gradually tumors like hemangiomas (Pardali et al. 2010; acquire a lumen (Ferguson et al. 2005). Vasculo- Akhurst and Hata 2012). The importance of the genesis ends with the formation of a honey- TGF-b signaling pathways in the spatial and tem- comb-like primary vascular plexus. During poral regulation of heart and blood vessel mor- angiogenesis (Fig. 1), the primarycapillary plex- phogenesis, as well as cardiovascular homeosta- us is remodeled into a stable hierarchical sis, is evident when analyzing the phenotypes of branched network, containing arteries, capillar- mice deficient in components of the TGF-b sig- ies, and veins. Vascularendothelialgrowth factor naling cascade (Goumans and Mummery 2000; (VEGF) signaling is a key pathway involved in Goumans et al. 2009). The multifunctional and vascular remodeling, as VEGF loosens cell–cell context-dependent activities of TGF-b and its contacts within the newly formed capillaries and interactions with nonvascular cells (e.g., im- causes local degradation of the ECM. Activated mune cells) complicate the interpretation of its ECs start to proliferate in response to VEGF or in vivo roles in cardiovascular biology. In this basic fibroblast growth factor (bFGF or FGF-2), review, we only focus on TGF-b as the role of and form a new sprout (Fig. 1). Loosening of BMP in angiogenesis is discussed elsewhere cell–cell contacts can also result in fusion of (Goumans et al. 2017). First, we discuss vascular capillaries to form arteries and veins. development and TGF-b signaling, followed by The final step in vascular development is the mechanisms that are at the basis of TGF-b’s initiated by the blood circulation. In this phase, control of vascular function, its effects on endo- nonfunctional sprouts that were unable to fuse thelial cells (ECs), smooth muscle cells (SMCs), to patent passages are pruned. The remaining and pericytes, and how a misbalance in TGF-b vessels are shaped and remodeled by the blood signaling leads to vascular dysfunction. flow to suit local tissue needs (Adams and Ali- talo 2007; Carmeliet and Jain 2011). VEGF is also steering vascular remodeling and pruning. BLOOD AND LYMPHATIC VASCULAR Once this process is finished, TGF-b and plate- NETWORK FORMATION let-derived growth factor (PDGF)-BB are secret- ed by the endothelium and stabilize the mature The Vascular System vascular network (Fig. 1). TGF-b stimulates the The heart, blood, and blood vessels make up the production and stabilization of the ECM and, vascular system, which supplies oxygen and nu- together with PDGF-BB, attracts and regulates trients to all cells of the body and removes waste the differentiation of pericytes and SMCs, which products (Potente et al. 2011). This is achieved surround and enclose the primitive vascular by pumping blood through a highly branched tube (Bergers and Song 2005). Finally, TGF-b vascular network of specialized blood vessels promotes arterial-venous specification neces- (i.e., arteries, capillaries, and veins). Blood ves- sary for the establishment and enlargement of sels are lined with a single layer of ECs, and arteries and veins (Fish and Wythe 2015). stabilized by a basal lamina and a layer of con- Although vasculogenesis occurs mainly nective tissue containing SMCs or pericytes. during embryonic development, angiogenesis The amount of connective tissue and number is responsible for the formation of new blood of smooth muscles cells or pericytes present in vessels after birth. Angiogenesis will result in the vessel wall depends on the diameter of the vascularization of growing tissues and during vessel and its function. healing, and in the formation of capillaries, 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a022210 Downloaded from http://cshperspectives.cshlp.org/ Advanced Online Article. Cite this article as Endothelial cell lineage Mesenchyme commitment and differentiation ECM VEGF PDGF-BB LTBP Mature TGF-β onSeptember29,2021-PublishedbyColdSpringHarborLaboratoryPress LAP Cold Spring Harb Perspect Biol Mesoderm Angioblasts Endothelial cell Endothelial cells recruit mural cell progenitors TGF-β TGF- doi: 10.1101 Smooth muscle cell b differentiation Signaling in Cardiovascular Function Smooth muscle cell / cshperspect.a022210 Figure 1. Process of vasculogenesis. Vasculogenesisstarts with the differentiation and proliferation of mesodermal cells into angioblasts followed by their differentiation into endothelial cells (ECs) in response to vascular endothelial growth factor (VEGF). These ECs fuse and form a lumen in a honeycomb structure. Platelet-derived growth factor (PDGF) secreted by ECs induces recruitment of mesenchymal cells that will differentiate into smooth muscle cells (SMCs) or pericytes. When SMCs or pericytes adhere to ECs, the ECs start to produce TGF-b. TGF-b is produced as a prepropolypeptide, which is proteolytically processed, and forms a small latent TGF-b complex consisting of the mature TGF-b dimer associated with two latency-associated peptides (LAPs). The small latent TGF-b complex binds to latent transforming growth factor b binding protein (LTBP),and this complex is secreted as the large latent TGF-b complex. LTBPbinds to extracellular matrix (ECM) proteins such as fibronectin. Activation of TGF-b by, for example, proteolytic release from LAP will induce growth arrest and terminal differentiation of SMCs. 3 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor