Endothelial effects of atrial natriuretic peptide (ANP) prevent pulmonary arterial remodelling and hypertension

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Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse origins. Endothelial cell dysfunction is (co)causally involved in the pathogenesis of idiopathic and familial PAH, but the specific mechanisms are unclear. The beneficial effect of drugs preventing cyclic GMP (cGMP) degradation (sildenafil) or stimulating cGMP production (activators of the nitric oxide/NO- regulated guanylyl cyclase) suggests that impaired vascular cGMP signaling is critically involved in the development of pulmonary vascular remodelling and constriction. Besides NO, atrial (ANP) and B-type natriuretic peptides (BNP), via their shared guanylyl cyclase A (GC-A) receptor, stimulate cGMP production in all types of pulmonary vascular cells (i.e. endothelia (EC), smooth muscle cells (SMC) and fibroblasts). Notably, our studies showed that mice with either global or conditional, EC-restricted deletion of the GC-A receptor develop marked PAH already under resting conditions, with increased right ventricular (RV) systolic pressure, RV hypertrophy, enhanced muscularization of small pulmonary arteries and pulmonary arteriolar rarefaction. In contrast, SMC-specific ablation of GC-A did not provoke pulmonary alterations. Thus, expression and function of GC-A in ECs is critical to prevent pulmonary vascular remodelling and PAH. Here we propose molecular and functional studies in EC GC-A KO and control mice to dissect the effects of the endothelial ANP/GC-A/cGMP pathway on pulmonary EC proliferation/viability and on the paracrine crosstalk between EC and SMC or inflammatory cells. These in vivo/ex vivo studies will be complemented with studies on cultured human and murine pulmonary EC and SMC, to further our understanding of the cause and pathogenesis of PAH, i.e. the role of endothelial natriuretic peptide signaling.