The
nitric oxide (NO)-cGMP signal transduction pathway plays an important role in the regulation of pulmonary vascular tone and resistance in
pulmonary hypertension. A number of studies have demonstrated that endothelial (e) and inducible
nitric oxide synthases (NOS) are upregulated in
hypoxia-exposed rat lung. These changes in NOS expression have been found to correlate with the process of pulmonary
vascular remodeling in
hypoxia-induced
pulmonary hypertension, and remodeling is increased in the absence of eNOS. In this study, we examined the expression and localization of
soluble guanylate cyclase (sGC), the primary receptor for NO, in
hypoxia- and normoxia-treated rat lungs. Male Sprague-Dawley rats were exposed to
hypoxia (10% O(2), normobaric) or normoxia for 1, 3, 5, and 21 days. The lungs were used for Western analysis of sGC
protein, sGC
enzyme activity, immunohistochemistry using antiserum against sGC alpha(1)- and beta(1)-subunits, and nonradioactive in situ hybridization (NRISH) using a
digoxigenin-labeled sGC alpha(1)-subunit
cRNA probe. Western blot analysis revealed a more than twofold increase of sGC
protein alpha(1)-subunit in rat lungs exposed to 3, 5, and 21 days of
hypoxia, correlating well with sGC
enzyme activity. Immunohistochemistry and NRISH demonstrated increased expression of sGC in the smooth muscle cells of the pulmonary arteries and arterioles in the hypoxic rat lungs when compared with normoxic controls. Based on our results, the upregulation of sGC may play an important role in the regulation of smooth muscle tone and pressure in the pulmonary circulation during chronic
hypoxia.