Pulmonary vascular remodeling and endothelial proliferation are important pathophysiological processes contributing to increased vascular resistance seen with pulmonary hypertension (PH). C-type natriuretic peptide (CNP) is an endothelium derived natriuretic peptide that has been shown to have anti-inflammatory, anti-mitogenic and anti-proliferative actions. However, its role in modulating severe PH is not known. We hypothesized that CNP will attenuate severe PH through its effect on pulmonary vascular remodeling. In order to test our hypothesis we chose to study the effect of continuous infusion of CNP, delivered by an osmotic pump, in a rat model of severe PH. This model combines the use of a VEGF receptor blocker, SU5416 (SU), and hypoxia to induce severe PH and plexiform lesions. Adult male Sprague Dawley rats were implanted with osmotic pumps to deliver CNP or vehicle for three weeks. Subsequently they received a single dose of SU or diluant and were placed in either normoxic or hypoxic (10% FiO
2
) environment for 3 wks. the animals then underwent echocardiogram, right heart catheterization, and carotid catheterization to evaluate right ventricle (RV) function, RV mass, and RV pressure (RVP). The lungs were fixed and evaluated for vascular remodeling using H&E staining and immunohistochemistry. Rats exposed to hypoxia alone developed moderate PH, while animals given SU and exposed to hypoxia developed severe PH (RVP (mmHg)- Normoxia: 27±1; Hypoxia: 79±6; Hypoxia+SU: 92±3). RV hypertrophic response mirrored the RVP in each group. Animals with severe PH receiving low dose CNP (0.75μg/hr) had increased RV mass and RVP, similar to vehicle treated animals, but demonstrated a 19% reduction in the microvascular wall thickness (p<0.05 compared to vehicle). Upon treatment with a higher dose of CNP (2.25μg/hr), animals demonstrated a significant reduction in RVP in the severe PH group (76±5 mmHg), as compared to vehicle treated animals (95±6 mmHg, p<0.05). CNP attenuates severe pulmonary hypertension likely via its effects on microvascular remodeling.
Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function
