Endothelin-1 and Serotonin are Involved in Activation of RhoA/Rho Kinase Signaling in the Chronically Hypoxic Hypertensive Rat Pulmonary Circulation

Abstract

We have previously reported that vasoconstrictor sensitivity to KCl (a receptor-independent and voltage-gated Ca influx-mediated vasoconstrictor) is augmented in the chronically hypoxic hypertensive rat pulmonary circulation probably through increased Rho kinase-mediated Ca sensitization. However, the upstream mechanism by which the RhoA/Rho kinase signaling pathway is activated is unknown. This study examined if endogenous endothelin-1 (ET-1) and serotonin (5-HT) play roles in the Rho kinase-mediated augmented vasoconstrictor response to KCl and the activation of RhoA in chronically hypoxic hypertensive rat pulmonary arteries. The augmented KCl vasoconstriction in hypertensive lungs was reduced by the ETA receptor antagonist BQ123, while a dual ETA/B antagonist had no further effects. A combination of BQ123 and a 5-HT1B/1D receptor antagonist, GR127935, was more effective than either agent alone. The combined antagonists also reduced augmented contractile sensitivity to KCl in hypertensive intrapulmonary arteries. Membrane-to-cytosol ratio of RhoA expression in hypertensive arteries was greater than that in normotensive arteries and was reduced by BQ123 and GR127935. These results suggest that stimulation of ETA and 5-HT1B/1D receptors by endogenous ET-1 and 5-HT, respectively, is involved in RhoA/Rho kinase-mediated increased Ca sensitization in the chronically hypoxic hypertensive rat pulmonary circulation.

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

“…Although evidence supports a role of pulmonary VSMC phenotypic switch in the pathogenesis PH, an imbalance between pulmonary vasoconstrictors such as ET-1 and vasodilators such as NO and PGI 2 has also been implicated in PH (19,26,33,34,38,64), and vasodilators are a major component of the current therapy for PH (10,47,71,80). However, a large number of patients do not respond to vasodilators, possibly because of excessive pulmonary vascular remodeling.…”

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

“…This may be attributable to the involvement of ROCK in the pathogenesis of experimental PH induced by different stimuli [10,13,15,16]. Moreover, ROCK signalling is implicated in the beneficial effects of therapeutic approaches targeting signalling cascades other than ROCK [12,13,19,[47][48][49]. It seems likely, therefore, that ROCK may be the convergent point for various signalling cascades implicated in the pathogenesis of PH.…”

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

“…Conversely, we reported that the loss of nitric oxide production in endothelial cells during chronic hypoxia is critical in the induction of PH (16,17). In addition, chronic hypoxia directly affects the contractile ability of pulmonary smooth muscle cells (18,19). However, the phenotype of contractility is erratic in the pulmonary artery of PH (20 -22).…”