DEVELOPMENTAL REGULATION OF ANGIOTENSIN-CONVERTING ENZYME AND ANGIOTENSIN TYPE-1 RECEPTOR IN THE RAT PULMONARY CIRCULATION

Factors that influence the development of the normal pulmonary vascula ture are poorly understood. Since increased local production of angiot ensin II (AII) by angiotensin converting enzyme (ACE) has been implica ted in the medial hypertrophy of systemic and pulmonary hypertension, we questioned whether ACE and angiotensin receptor expression may infl uence the muscularization of the normal pulmonary vasculature during d evelopment. The approach employed measurement of lung ACE activity, as sessment of local ACE expression by immunohistochemistry, and angioten sin type 1 receptor (AT(1)) expression by in situ hybridization in rat lungs ranging from 15 days of intrauterine life (term = 21 d) to adul thood. The temporal and spatial pattern of ACE expression was compared with that of the endothelial marker, von Willebrand factor (vWF), and the smooth muscle cell markers, alpha smooth muscle actin and smooth muscle myosin. ACE activity was first detected in lung homogenates on day 17 of gestation (1 +/- 0.2 mU/mg) and increased progressively to t erm (27.7 +/- 3.2 mU/mg). However, the greatest increase in lung ACE a ctivity to adult levels (379 +/- 25.2 mU/mg) occurred between 2 and 4 wk of postnatal life. Immunohistochemistry demonstrated vWF expression by vascular endothelium throughout the lung as early as day 15 of ges tation. In contrast, ACE expression was observed in the endothelium of only hilar pulmonary arteries on day 15 of gestation, and thereafter was noted to be expressed in endothelial cells of progressively more d istal arteries, such that by term, endothelial cells of all musculariz ed arteries expressed ACE. Alveolar capillary ACE expression was not d etected until day 20 of gestation, and increased dramatically after bi rth. Smooth muscle actin expression in lung arteries closely parallele d the expression of endothelial ACE. AT(1) receptor mRNA was first exp ressed in the peripheral lung on day 17 of gestation by non-epithelial undifferentiated mesenchyme. In contrast, AT(1) mRNA signal was much reduced in differentiated smooth muscle. We speculate that ACE express ion in the fetal lung circulation may influence the muscularization of fetal pulmonary arteries by the interaction of locally produced angio tensin II with the AT(1) receptor.