Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by vascular malformations. Many affected individuals develop recurrent nosebleeds, which can severely affect their quality of life and are clinically difficult to treat. We report here that treatment with thalidomide reduced the severity and frequency of nosebleeds (epistaxis) in the majority of a small group of subjects with HHT tested. The blood hemoglobin levels of the treated individuals rose as a result of reduced hemorrhage and enhanced blood vessel stabilization. In mice heterozygous for a null mutation in the Eng gene (encoding endoglin), an experimental model of HHT, thalidomide treatment stimulated mural cell coverage and thus rescued vessel wall defects. Thalidomide treatment increased platelet-derived growth factor-B (PDGF-B) expression in endothelial cells and stimulated mural cell activation. The effects of thalidomide treatment were partially reversed by pharmacological or genetic interference with PDGF signaling from endothelial cells to pericytes. Biopsies of nasal epithelium from individuals with HHT treated or not with thalidomide showed that similar mechanisms may explain the effects of thalidomide treatment in humans. Our findings demonstrate the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations.

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…[28][29][30][31] . Attention now focuses on aberrant vascular responses to injury-induced angiogenic stimuli, when the mutated genes in HHT appear to result in the inability of a blood vessel to mature appropriately.…”

“…Attention now focuses on aberrant vascular responses to injury-induced angiogenic stimuli, when the mutated genes in HHT appear to result in the inability of a blood vessel to mature appropriately. 28,30,31 In man, HHT-specific pathology develops in different contexts according to the repertoire of susceptibility genes and/or environmental triggers to which each individual is exposed.…”

“…Endoglin is a relatively endothelial specific co-receptor for multiple receptor complexes of the TGF-ß superfamily 137 Recent HHT concepts include the "balance hypothesis" whereby the HHT mutations modify the predominant endothelial TGF-ß type I receptor, Smad pathway, and ultimately endothelial cell response, [144][145][146][147] and models incorporating BMP9 and BMP10 which are specific ALK-1 ligands that can also bind endoglin [148][149][150] . The most recent models indicate a return to TGF-ß1 rather than BMP9/10 causality in HHT 31 . Which ligand-receptor complexes contribute to HHT pathogenesis however, remains the subject of intense research 151,152 .…”

“…Attention now focuses on aberrant vascular responses to injury-induced angiogenic stimuli, when the mutated genes in HHT appear to result in the inability of a blood vessel to mature appropriately. 28,30,31 In man, HHT-specific pathology develops in different contexts according to the repertoire of susceptibility genes and/or environmental triggers to which each individual is exposed.Furthermore, as illustrated in Figure 1 and Table 1, the spectrum of HHT encompasses multiple organ systems and within these, numerous forms of disease. HHT therefore spans a vast range of scientific and clinical disciplines, and is an extremely challenging disorder both to understand, and to manage.…”

ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation

“…However, it is now established that inflammatory cytokines play a crucial role in initiating microvascular damage (Nian et al, 2004). Cytokines such as TNF, IL-1, and IL-6 are induced soon after myocardial ischemia, triggering leukocyte transmigration, platelet adhesion, and local generation of reactive the Cspg4 promoter, allowing selective detection of pericytes and smooth muscle cells in the periphery (Zhu et al, 2008;Lebrin et al, 2010). These mice were crossed with the proNgf-HA/ + mice to generate NG2DsRedBAC;proNgf-HA/ + mice.…”