Time-Dependent Phenotypic and Contractile Changes of Pulmonary Artery in Chronic Hypoxia–Induced Pulmonary Hypertension

Abstract

Abstract. Phenotypic and contractile changes in pulmonary arterial smooth muscle cells (PASMCs) were examined in rats with pulmonary hypertension induced by hypoxia. Exposure to hypoxia induced pulmonary hypertension within 1 -4 weeks. Staining with BrdU revealed that proliferative activities of PASMCs peaked at 1 week of hypoxic exposure, and then moderate proliferative activity was maintained for the next 2 -4 weeks. The β-actin/α-actin ratio also increased at 1 -2 weeks of exposure to hypoxia. Absolute contractility of the pulmonary arterial ring continuously decreased during hypoxia, whereas the basal active tonus of the pulmonary artery increased at 1 -3 weeks. Nicardipine, the ET A -receptor antagonis, CI-1034 and the rhokinase inhibitor Y27632 partially inhibited the elevated active tonus. Endothelin-1 content in the pulmonary hypertensive lung was continuously increased during exposure to hypoxia. In conclusion, the hypoxia-induced proliferative activity of PASMCs comprised a transient phase followed by a sustained phase. The change in PASMCs from a contractile to a synthetic phenotype also correlated with proliferative activity, which subsequently decreased PASMC contractility. The continuous production of endothelin-1 upon hypoxic exposure might contribute to the increased basal tonus of the pulmonary arterial wall, which might subsequently increase pulmonic arterial pressure, resulting in accelerated pulmonary hypertension.

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

“…In other experiments, the tissues were precontracted with Phe (10 Ϫ5 M), increasing concentrations (10 Ϫ9 to 10 Ϫ5 M) of acetylcholine (ACh) were added, and the % relaxation of Phe contraction was measured. Parallel contraction and relaxation experiments were performed in endotheliumintact vascular rings pretreated with the NO synthase (NOS) inhibitor N -nitro-L-arginine methyl ester (L-NAME, 3 ϫ 10 Ϫ4 M) or the guanylate cyclase inhibitor 1H- [1,2,4] Lung histology and morphometric analysis. In a subset of experimental animals, the lungs were perfused with PBS through the right ventricle to remove the blood from the pulmonary vessels, fixed with cold 4% paraformaldehyde through the trachea, then excised and fixed in 4% paraformaldehyde overnight at 4°C followed by paraffin em- Data represent means Ϯ SE of cumulative data from 6 -12 rats.…”

“…Differences were considered statistically significant if P Ͻ 0.05. 4 Cl treatment on body weight, acid-base status, and hematocrit. Initial body weight in all rats was 250 -300 g. Treatment of rats under normoxia with NH 4 Cl for 5 days did not significantly affect body weight (Table 1).…”

“…Also, it is increasingly appreciated that alternative approaches such as antiproliferative, proapoptotic, or immunomodulatory therapies hold promise in further improving the outcome of PH (5,18,36,52,54,64,77). Importantly, accumulating evidence supports that a phenotypic switch of pulmonary VSMCs from a contractile to a proliferative phenotype may contribute to the pathogenesis of PH (4,24,45,48,53), and reversal of this pathology could enhance the effectiveness of vasodilator therapies.Rodent models of experimental PH recapitulate to a certain extent the histological features of human PH and provide a useful tool to study the efficacy of novel therapeutic approaches (17,31,46,65). The hypoxic and monocrotaline (MCT) rat models are particularly useful in the evaluation of antiproliferative and proapoptotic therapies since medial hypertrophy of the pulmonary arterioles is a key feature in these PH models (36,52,54,64).…”

“…Also, it is increasingly appreciated that alternative approaches such as antiproliferative, proapoptotic, or immunomodulatory therapies hold promise in further improving the outcome of PH (5,18,36,52,54,64,77). Importantly, accumulating evidence supports that a phenotypic switch of pulmonary VSMCs from a contractile to a proliferative phenotype may contribute to the pathogenesis of PH (4,24,45,48,53), and reversal of this pathology could enhance the effectiveness of vasodilator therapies.…”

“…The present study was designed to test the hypothesis that nonhypercapnic acidosis is protective in experimental PH by improving pulmonary artery reactivity and by decreasing hypertrophic remodeling. We measured the hemodynamics and examined the pulmonary arterial function in hypoxia and MCT-induced rat models of PH chronically treated or nontreated with NH 4 Cl to determine whether 1) nonhypercapnic acidosis improves hemodynamic parameters and ameliorates RVH in experimental PH, 2) mild acidosis improves pulmonary arterial relaxation via the endothelium-dependent NOcGMP pathway in PH, 3) the pulmonary VSMC responsiveness to vasodilators is enhanced during nonhypercapnic acidosis in experimental PH, and 4) the beneficial effects of acidosis in experimental PH could be related to decreased pulmonary arterial remodeling.…”