Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder in humans that is characterised by multisystemic vascular dyplasia and recurrent haemorrhage. Germline mutations in one of two different genes,endoglin or ALK1 can cause HHT. Both are members of the transforming growth factor (TGF) β receptor family of proteins, and are expressed primarily on the surface of endothelial cells (ECs). Mice that lack endoglin or activin receptor like kinase (ALK) 1 die at mid-gestation as a result of defects in the yolk sac vasculature. Here, we have analyzed TGFβsignalling in yolk sacs from endoglin knockout mice and from mice with endothelial-specific deletion of the TGFβ type II receptor (TβRII)or ALK5. We show that TGFβ/ALK5 signalling from endothelial cells to adjacent mesothelial cells is defective in these mice, as evidenced by reduced phosphorylation of Smad2. This results in the failure of vascular smooth muscle cells to differentiate and associate with endothelial cells so that blood vessels remain fragile and become dilated. Phosphorylation of Smad2 and differentiation of smooth muscle can be rescued by culture of the yolk sac with exogenous TGFβ1. Our data show that disruption of TGFβsignalling in vascular endothelial cells results in reduced availability of TGFβ1 protein to promote recruitment and differentiation of smooth muscle cells, and provide a possible explanation for weak vessel walls associated with HHT.

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“… HHT mutations (endoglin and ALK-1) impair recruitment of mural cells to vessels, 160,164 at least in part via reduced endothelial cell secretion of TGF-ß1 168,169 and/or reduced TGF-ß1 induced responses. 160,168 Endogenous Smad phosphorylation in mural cells is reduced, 168 29,173 Support for a fundamental role for aberrant angiogenesis and reactive oxygen species in HHT disease pathogenesis is accumulating in man, with case reports and small series suggesting that anti-angiogenic and anti-oxidant strategies may be of therapeutic benefit in HHT (see Sections 4 and 5 below).…”

“…160,168 Endogenous Smad phosphorylation in mural cells is reduced, 168 29,173 Support for a fundamental role for aberrant angiogenesis and reactive oxygen species in HHT disease pathogenesis is accumulating in man, with case reports and small series suggesting that anti-angiogenic and anti-oxidant strategies may be of therapeutic benefit in HHT (see Sections 4 and 5 below).…”

The brain tumor microenvironment

“…TGF-b signaling plays an important role during vascular development and is known to maintain proper endothelial pericyte/ VSM cell interactions. TGF-b signaling in endothelial cells further drives the expression, synthesis, and release of TGF-b to nearby VSM cells to influence their differentiation (Carvalho et al, 2004;Wurdak et al, 2005). Studies suggest the importance of juxtaposed intercellular communication between endothelial cells and pericytes/ VSM cells for activation of the TGF-b pathway (Antonelli-Orlidge et al, 1989;Sato et al, 1990).…”

Activin Receptor-Like Kinase 5 Inhibition Reverses Impairment of Endothelial Cell Viability by Endogenous Islet Mesenchymal Stromal Cells

“…The importance of TGF-b signaling in the cardiovascular system is underlined by the observation that genetic deletion of several TGF-b family members, their receptors, or downstream signaling molecules results in death of the mutants because of severe defects in the yolk sac vasculature [29]. In this study, we have demonstrated that: (a) EC gene expression is diminished and TGF-bI/ TGF-b1R expression is upregulated in isolated islets maintained in culture; (b) islets contain two distinct populations of cells expressing the TGF-b accessory receptor endoglin, one of which coexpresses the EC marker CD31 in situ; (c) an endoglin-positive, MSC population expanded from human islets disrupts the proangiogenic properties of microvascular ECs and inhibits EC survival in vitro; these changes are associated with increased Smad2 phosphorylation, and (d) pharmacological inhibition of TbRI/ ALK5 improves EC survival in cultured islets and reduces the detrimental effects of MSCs on cocultured ECs.…”

“…For example, studies in genetically modified mice revealed a TGF-b-mediated autoregulatory loop between ECs and MSCs, such that disrupted TGFb signaling in ECs impaired TGFb-driven ALK5 signaling in adjacent mesenchymal cells, inhibiting their differentiation into vascular smooth muscle cells and their association with developing endothelial tubes [29]. Also, coculture of bone marrow-derived MSCs with adult ECs on Matrigel causes EC cytotoxicity, resulting in capillary network breakdown [51].…”