In vitro effects of vasodilatory drugs on BMPR2-silenced pulmonary microvascular endothelial cell function

Abstract

Mutations and impairment of the bone morphogenetic protein receptor type 2 (BMPR2) gene and signalling pathway are observed in heritable and idiopathic pulmonary arterial hypertension (PAH). In PAH, endothelial dysfunction is currently treated by vasodilatory therapies targeting the endothelin (ET-1), nitric oxide (NO) and prostacyclin (PGI₂) pathways. Experimental and clinical evidence about the role of angiogenesis and potential effects of PAH-specific vasodilatory therapies remain inconclusive. We aim to investigate in vitro whether i) BMPR2 silencing can impair angiogenic capacity of human lung microvascular endothelial cells (HLMVECs) and ii) PAH-specific vasodilatory therapies can restore them. The effects of macitentan, tadalafil and selexipag, respectively targeting ET-1, NO and PGI₂ pathways, on BMPRII downstream effector activation, endothelial barrier function and angiogenesis were investigated in BMPR2-silenced HLMVECs. Stable BMPR2 silencing in HLMVECs resulted in impaired 2D-migration and 3D-tube formation in vitro capacity. Inhibition of ET-1 pathway by macitentan was able to partially restore tube formation in BMPR2-silenced HLMVECs, whereas none of the therapies were able to restore endothelial barrier function. Any deleterious effects of inhibiting ET-1 or activating NO and PGI₂ pathways were observed. Our findings highlight the potential role of BMPRII in pulmonary microvascular endothelial cell angiogenesis. In addition, PAH-specific vasodilatory drugs display limited effects on endothelial function when BMPRII is impaired, suggesting that innovative therapeutic strategies targeting BMPRII signalling are needed to better rescue endothelial dysfunction in PAH.