Genetic deletion of the endothelial GC-A receptor in mice caused pulmonary hypertension and vascular remodeling, which was reversed by AT1-receptor blockade with losartan.
Does endothelial ANP/GC-A signaling prevent pulmonary vascular remodeling and pulmonary hypertension in mice?
Endothelial ANP/GC-A signaling is critical to prevent pulmonary vascular remodeling and pulmonary hypertension, and its dysfunction activates the ACE-angiotensin pathway.
The cardiac hormone atrial natriuretic peptide (ANP) regulates systemic and pulmonary arterial blood pressure by activation of its cyclic GMP-producing guanylyl cyclase-A (GC-A) receptor. In the lung, these hypotensive effects were mainly attributed to smooth muscle-mediated vasodilatation. It is unknown whether pulmonary endothelial cells participate in the homeostatic actions of ANP. Therefore, we analyzed GC-A/cGMP signalling in lung endothelial cells and the cause and functional impact of lung endothelial GC-A dysfunction. Western blot and cGMP determinations showed that cultured human and murine pulmonary endothelial cells exhibit prominent GC-A expression and activity which were markedly blunted by hypoxia, a condition known to trigger pulmonary hypertension (PH). To elucidate the consequences of impaired endothelial ANP signalling, we studied mice with genetic endothelial cell-restricted ablation of the GC-A receptor (EC GC-A KO). Notably, EC GC-A KO mice exhibit PH already under resting, normoxic conditions, with enhanced muscularization of small arteries and perivascular infiltration of inflammatory cells. These alterations were aggravated on exposure of mice to chronic hypoxia. Lung endothelial GC-A dysfunction was associated with enhanced expression of angiotensin converting enzyme (ACE) and increased pulmonary levels of Angiotensin II. Angiotensin II/AT1-blockade with losartan reversed pulmonary vascular remodelling and perivascular inflammation of EC GC-A KO mice, and prevented their increment by chronic hypoxia. This experimental study indicates that endothelial effects of ANP are critical to prevent pulmonary vascular remodelling and PH. Chronic endothelial ANP/GC-A dysfunction, e.g. provoked by hypoxia, is associated with activation of the ACE-angiotensin pathway in the lung and PH.
Werner et al. (Wed,) conducted a other in Pulmonary hypertension. Endothelial GC-A deletion and Losartan vs. Control littermates and Vehicle was evaluated on Right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling. Genetic deletion of the endothelial GC-A receptor in mice caused pulmonary hypertension and vascular remodeling, which was reversed by AT1-receptor blockade with losartan.