Endoglin in angiogenesis and vascular diseases

Abstract

Endoglin is a transmembrane auxillary receptor for transforming growth factor-beta (TGF-beta) that is predominantly expressed on proliferating endothelial cells. Endoglin deficient mice die during midgestation due to cardiovascular defects. Mutations in endoglin and activin receptor-like kinase 1 (ALK1), an endothelial specific TGF-beta type I receptor, have been linked to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vascular dysplasia characterized by telangiectases and arteriovenous malformations. Endoglin heterozygote mice develop HHT-like vascular abnormalities, have impaired tumor and post-ischemic angiogenesis and demonstrate an endothelial nitric oxide synthase-dependent deterioration in the regulation of vascular tone. In pre-eclampsia, placenta-derived endoglin has been shown to be strongly upregulated and high levels of soluble endoglin are released into the circulation. Soluble endoglin was found to cooperate with a soluble form of vascular endothelial growth factor receptor 1 in the pathogenesis of pre-eclampsia by inducing endothelial cell dysfunction. Endoglin is highly expressed in tumor-associated endothelium, and endoglin antibodies have been successfully used to target activated endothelial cells and elicit anti-angiogenic effects in tumor mouse models. These exciting advances provide opportunities for the development of new therapies for diseases with vascular abnormalities.

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

“…Also, in clinical development as an antitumor agent is a chimeric antibody (TRACON) capable of neutralizing endoglin (CD105; ref. 31), a proangiogenic protein in the TGFb superfamily that binds BMP9/BMP10 (22,45,46), with loss-of-function mutations resulting in another type of vascular dysplasia, HHT-1 (15,47). In patients with advanced, refractory tumors (31), anti-endoglin antibody was associated with infusion reactions and immunogenicity distinct from effects described for dalantercept in the present study, whereas other adverse effects such as anemia and telangiectasias were observed in both studies.…”

Novel Angiogenic Factors for Predicting Preeclampsia: sFlt-1, PlGF, and Soluble Endoglin~!2008-08-29~!2008-12-15~!2009-01-02~!

“…Endoglin is highly expressed on the cell membranes of syncytiotrophoblasts, vascular endothelial cells, and it is also expressed on other cells such as monocytes and hematopoietic stem cells [49][50][51][52]. Given that, Endoglin is suggested to involve in angiogenesis and hematopoiesis and play a role in cancer and cardiovascular development [53,54]. In human, mutations in the Endoglin gene cause hereditary hemorrhagic telangiectasia or Osler Rendu Weber Syndrome type 1 (HHT1), an autosomal-dominant disorder characterized by arteriovenous malformations in multiple organ systems and bleeding telangiectases of mucous membranes [54].…”

“…Given that, Endoglin is suggested to involve in angiogenesis and hematopoiesis and play a role in cancer and cardiovascular development [53,54]. In human, mutations in the Endoglin gene cause hereditary hemorrhagic telangiectasia or Osler Rendu Weber Syndrome type 1 (HHT1), an autosomal-dominant disorder characterized by arteriovenous malformations in multiple organ systems and bleeding telangiectases of mucous membranes [54].…”

Nitric Oxide Formation Is Inversely Related to Serum Levels of Antiangiogenic Factors Soluble Fms-Like Tyrosine Kinase-1 and Soluble Endogline in Preeclampsia

“…33,34 Interestingly, endoglin modulates endothelial NO synthase (eNOS) expression and activity, thus affecting vascular tone. [35][36][37] In the present study, we hypothesized that lower concentrations of relevant markers of NO formation (plasma and whole blood nitrite) would be found in hypertensive disorders of pregnancy compared with those found in healthy pregnancies. In addition, given the fact that sFLT-1 and sEng interfere with eNOS activity, we hypothesized that inverse relationships exist between the circulating concentrations of markers of NO formation and sFLT-1 or sEng during pregnancy.…”