Abstract
Endoglin (CD105) is an auxiliary receptor for members of the TFG-β superfamily. Whereas it has been demonstrated that the deficiency of endoglin leads to minor and defective angiogenesis, little is known about the effect of its increased expression, characteristic of several types of cancer. Angiogenesis is essential for tumor growth, so high levels of proangiogenic molecules, such as endoglin, are supposed to be related to greater tumor growth leading to a poor cancer prognosis. However, we demonstrate here that endoglin overexpression do not stimulate sprouting or vascularization in several in vitro and in vivo models. Instead, steady endoglin overexpression keep endothelial cells in an active phenotype that results in an impairment of the correct stabilization of the endothelium and the recruitment of mural cells. In a context of continuous enhanced angiogenesis, such as in tumors, endoglin overexpression gives rise to altered vessels with an incomplete mural coverage that permit the extravasation of blood. Moreover, these alterations allow the intravasation of tumor cells, the subsequent development of metastases and, thus, a worse cancer prognosis.
Highlights
Angiogenesis is the formation de novo of blood vessels from preexisting ones in response to several stimuli, mainly hypoxia
We demonstrate that sustained high levels of endoglin do not improve angiogenesis; instead, constitutive endoglin overexpression produces alterations in the structure of the vasculature
These alterations do not seem to be due to defects during the first phases of angiogenesis but endoglin overexpression alters vessel stabilization and maturation, as shown in vitro and in vivo
Summary
Angiogenesis is the formation de novo of blood vessels from preexisting ones in response to several stimuli, mainly hypoxia. There is a substantial amount of evidence that relates endoglin to angiogenesis. Endoglin expression is increased in the endothelium during active angiogenesis [5], at the angiogenic edge, where sprouting takes place [6,7,8]. Deficiency in endoglin expression is responsible for hereditary hemorrhagic telangiectasia type-1 (HHT-1), a disease characterized by vascular malformations [9]. The lack of or deficiency in endoglin produces minor and defective angiogenesis due to alterations of ECs physiology [7, 10,11,12]. The effect of increased endoglin expression, described in pathologies such as cancer, on the function of ECs and angiogenesis has not been deeply studied
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