The fawn-hooded rat (FHR) raised from birth at the altitude in Denver acquires severe pulmonary hypertension (PH). However, neonates raised at sea level (3 weeks postnatal) and then transferred to Denver do not acquire PH. This suggests a developmental component in the pathogenesis of PH in this model. We investigated the role of the RhoA/Rho-kinase signaling pathway in postnatal lung development and the development of PH.
Aberrant RhoA/Rho-kinase signaling has been implicated in both systemic and PH. This pathway also plays important roles in a wide variety of cell functions central to embryonic and neonatal development, including proliferation, migration, and differentiation. FHR pups were raised in normoxia (sea level, 0 m) or mild hypoxia (the altitude at Denver, 1,500 m). Fasudil, a Rho-kinase inhibitor, was administered orally (30 mg/kg) from birth to rats raised in Denver. Lung tissue was collected at 1 week, 2 weeks, 3 weeks, and 4 weeks postnatally. RhoA, Rho-kinase, Rac1, and RhoE were measured by Western analysis.