title: Developmental regulation of angiotensin converting enzyme and angiotensin type 1 receptor in the rat pulmonary circulation.
abstract: Factors that influence the development of the normal pulmonary vasculature are poorly understood. Since increased local production of angiotensin II (AII) by angiotensin converting enzyme (ACE) has been implicated in the medial hypertrophy of systemic and pulmonary hypertension, we questioned whether ACE and angiotensin receptor expression may influence the muscularization of the normal pulmonary vasculature during development. The approach employed measurement of lung ACE activity, assessment of local ACE expression by immunohistochemistry, and angiotensin type 1 receptor (AT1) expression by in situ hybridization in rat lungs ranging from 15 days of intrauterine life (term = 21 d) to adulthood. 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 term (27.7 +/- 3.2 mU/mg). However, the greatest increase in lung ACE activity 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 gestation. 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 distal arteries, such that by term, endothelial cells of all muscularized arteries expressed ACE. Alveolar capillary ACE expression was not detected until day 20 of gestation, and increased dramatically after birth. Smooth muscle actin expression in lung arteries closely paralleled the expression of endothelial ACE. AT1 receptor mRNA was first expressed in the peripheral lung on day 17 of gestation by non-epithelial undifferentiated mesenchyme. In contrast, AT1 mRNA signal was much reduced in differentiated smooth muscle. We speculate that ACE expression in the fetal lung circulation may influence the muscularization of fetal pulmonary arteries by the interaction of locally produced angiotensin II with the AT1 receptor.
authors.affiliation: Department of Pediatrics, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: N W
authors.initials: NW
authors.lastname: Morrell
authors.forename: S S
authors.initials: SS
authors.lastname: Grieshaber
authors.forename: S M
authors.initials: SM
authors.lastname: Danilov
authors.forename: R A
authors.initials: RA
authors.lastname: Majack
authors.forename: K R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D015415:Biomarkers; D002196:Capillaries / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D005260:Female; D005333:Fetus / Q000166:cytology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology / Q000648:ultrastructure; D011652:Pulmonary Circulation / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D007703:Peptidyl-Dipeptidase A