TGF-β Is Required for Vascular Barrier Function, Endothelial Survival and Homeostasis of the Adult Microvasculature

Abstract

Pericyte-endothelial cell (EC) interactions are critical to both vascular development and vessel stability. We have previously shown that TGF-β signaling between EC and mural cells participates in vessel stabilization in vitro. We therefore investigated the role of TGF-β signaling in maintaining microvessel structure and function in the adult mouse retinal microvasculature. TGF-β signaling was inhibited by systemic expression of soluble endoglin (sEng) and inhibition was demonstrated by reduced phospho-smad2 in the adult retina. Blockade of TGF-β signaling led to increased vascular and neural cell apoptosis in the retina, which was associated with decreased retinal function, as measured by electroretinogram (ERG). Perfusion of the inner retinal vasculature was impaired and was accompanied by defective autoregulation and loss of capillary integrity. Fundus angiography and Evans blue permeability assay revealed a breakdown of the blood-retinal-barrier that was characterized by decreased association between the tight junction proteins zo-1 and occludin. Inhibition of TGF-β signaling in cocultures of EC and 10T1/2 cells corroborated the in vivo findings, with impaired EC barrier function, dissociation of EC from 10T1/2 cells, and endothelial cell death, supporting the role of EC-mesenchymal interactions in TGF-β signaling. These results implicate constitutive TGF-β signaling in maintaining the integrity and function of the adult microvasculature and shed light on the potential role of TGF-β signaling in vasoproliferative and vascular degenerative retinal diseases.

Tumor localization of an anti-TGF-β antibody and its effects on gliomas

“…Similar results were also obtained by Pan and colleagues who found no difference in angiogenesis, apoptosis or the number of tumor-infiltrating lymphocytes in tumors resulting from the two cell lines when injected into immunodeficient rats (27). Although no changes in microvessel density were observed in this study or published data, results from Dohgu et al (28) and Walshe et al (29) indicate that the functionality of vessels is affected by TGF-ß. TGF-ß can upregulate expression of VEGF which induces angiogenesis and levels of VEGF can affect normalization of blood vessels.…”

Role of shear-stress-induced VEGF expression in endothelial cell survival

“…In addition, the synthesis of the soluble isoforms by arterial ECs suggests that diffusibility is important for their functions. Thus, in addition to a role for VEGF in EC survival, the arterial endothelium could be the source of the low levels of circulating VEGF that have been shown to be necessary for the maintenance of vessel tone (Hood et al, 1998;Walshe et al, 2009).…”

Osteoarthritis in horses - Part 1: relationship between clinical and radiographic examination for the diagnosis

“…Although the cartilage presents a connective tissue with very specialized functions, with biomechanical characteristics such as load-bearing and shock absorption, the biomechanical properties depend on the completeness of the collagen network, as well as the synthesis and retention of proteoglycans (Eyre and Wu 1995;van Weeren and Brahma 2001). Once the degenerative process is started, it will stimulate the production of transforming growth factor-β (TGF-β), which is a multivalent cytokine composed of three homologous isoforms (1, 2 and 3) that stimulates the synthesis of collagen type II and proteoglycans (Grimaud et al 2002;Walshe et al 2009). Transforming growth factor-β signaling promotes the differentiation of mesenchymal stem cells into chondrocytes and allows the repair of defects in the cartilage.…”