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1 Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States; Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
2 Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States
3 Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California, United States
* To whom correspondence should be addressed. E-mail: ysgao{at}labiomed.org.
An increase in Rho kinase (ROCK) activity is implicated in chronic hypoxia-induced pulmonary hypertension. In the present study we determined the role of ROCKs in cGMP-dependent protein kinase (PKG) -mediated pulmonary vasodilation of fetal lambs exposed to chronic hypoxia. Fourth generation pulmonary arteries were isolated from near-term fetuses ( 140 days of gestation) delivered from ewes exposed to chronic high altitude hypoxia for ~ 110 days and from control ewes. In vessels constricted to endothelin-1, 8-Br-cGMP caused a smaller relaxation in chronically hypoxic (CH) vessels compared to controls. Rp-8-Br-PET-cGMPS, a PKG inhibitor, attenuated relaxation to 8-Br-cGMP in control vessels to a greater extent than in CH vessels. Y-27632, a ROCK inhibitor, significantly potentiated 8-Br-cGMP-induced relaxation of CH vessels and had only a minor effect in control vessels. The expression of PKG was increased but was not accompanied with an increase in the activity of the enzyme in CH vessels. The expression of type II ROCK and activity of ROCKs were increased in CH vessels. The phosphorylation of threonine (Thr)-696 and Thr-850 of the regulatory subunit MYPT1 of myosin light-chain phosphatase was inhibited by 8-Br-cGMP to a lesser extent in CH vessels than in controls. The difference was eliminated by Y-27632. These results suggest that chronic hypoxia in utero attenuates PKG-mediated relaxation in pulmonary arteries, partly due to inhibition of PKG activity and partly due to enhanced ROCK activity. Increased ROCK activity may inhibit PKG action through increased phosphorylation of MYPT1 at Thr-696 and Thr-850.
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