Summary Pulmonary vasodilators and prostacyclin therapy in particular, have markedly improved the outcome of patients with pulmonary hypertension (PH). Endothelial dysfunction is a key feature of PH, and we previously reported that treprostinil therapy increases number and proliferative potential of endothelial colony forming cells (ECFC) isolated from PH patients’ blood. In the present study, the objective was to determine how treprostinil contributes to the proangiogenic functions of ECFC. We examined the effect of treprostinil on ECFC obtained from cord blood in terms of colony numbers, proliferative and clonogenic properties in vitro, as well as in vivo vasculogenic properties. Surprisingly, treprostinil inhibited viability of cultured ECFC but did not modify their clonogenic properties or the endothelial differentiation potential from cord blood stem cells. Treprostinil treatment significantly increased the vessel-forming ability of ECFC combined with mesenchymal stem cells (MSC) in Matrigel implanted in nude mice. In vitro, ECFC proliferation was stimulated by conditioned media from treprostinil-pretreated MSC, and this effect was inhibited either by the use of VEGF-A blocking antibodies or siRNA VEGF-A in MSC. Silencing VEGF-A gene in MSC also blocked the pro-angiogenic effect of treprostinil in vivo. In conclusion, increased VEGF-A produced by MSC can account for the increased vessel formation observed during treprostinil treatment. The clinical relevance of these data was confirmed by the high level of VEGF-A detected in plasma from patients with paediatric PH who had been treated with treprostinil. Moreover, our results suggest that VEGF-A level in patients could be a surrogate biomarker of treprostinil efficacy.
The endothelium and its integrity are in the center of numerous cardiovascular, pulmonary and tumoral diseases. Several studies identified different circulating cellular sub-populations, which allow a noninvasive exploration of endothelial dysfunction. Furthermore, angiogenesis plays a major role in the biology of benign and malignant hematologic diseases. Among these biomarkers, circulating endothelial cells could be considered as a marker of endothelial injury and/or endothelial activation as well as vascular remodeling, whereas circulating endothelial progenitor cells would be only involved in the vascular regeneration. In the future, the quantification of circulating endothelial cells in many diseases could be a noninvasive biomarker used in diagnosis, prognostic and therapeutic follow-up of lung vasculopathy and/or residual disease of hematological malignancies.
En 1865, Trousseau etablissait un lien entre cancer, hypercoagulabilite et risque de thrombose. Plus d’un siecle plus tard, il est maintenant admis que l’activation de l’hemostase est un facteur cle dans la progression des pathologies malignes. En effet, les cellules tumorales exposant le facteur tissulaire induisent la generation de thrombine, principal activateur des plaquettes qui secretent des facteurs de croissance favorisant l’angiogenese ou la croissance tumorale. Ainsi, les traitements anticoagulants pourraient representer une therapeutique additive du traitement du le cancer. Plus qu’un effet anticoagulant, les heparines et plus particulierement les heparines de bas poids moleculaire (HBPM) possedent un effet antitumoral in vitro et dans des modeles experimentaux de cancer. Les HBPM ont des proprietes antiangiogenes et empechent l’adhesion des glycosaminoglycannes de surface des cellules cancereuses avec les plaquettes et les selectines endotheliales. Les HBPM inhibent egalement la degradation de la matrice intercellulaire par les cellules tumorales contribuant a l’invasion metastatique. Les etudes cliniques disponibles actuellement, bien que limitees, permettent d’envisager un effet benefique des HBPM sur la survie des patients cancereux. De nouvelles etudes dans des groupes de patients homogenes et cibles nous permettront de statuer sur le role des HBPM dans la progression de la maladie cancereuse et sur la survie des patients. Enfin, de nouveaux biomarqueurs cellulaires comme les cellules endotheliales circulantes et leurs progeniteurs pourraient nous aider a adapter les nouvelles therapeutiques ciblees du traitement contre le cancer.