NW Morrell, SS Grieshaber, SM Danilov, RA Majack and KR Stenmark
Department of Pediatrics, University of Colorado Health Sciences Center, Denver 80262, USA.

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.

This article has been cited by other articles:

				Y. Chen, A. Pearlman, Z. Luo, and C. S. Wilcox Hydrogen peroxide mediates a transient vasorelaxation with tempol during oxidative stress Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2085 - H2092. [Abstract] [Full Text] [PDF]

				S. Sarlos and J. L. Wilkinson-Berka The Renin-Angiotensin System and the Developing Retinal Vasculature Invest. Ophthalmol. Vis. Sci., March 1, 2005; 46(3): 1069 - 1077. [Abstract] [Full Text] [PDF]

				M Otsuka, H Takahashi, M Shiratori, H Chiba, and S Abe Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist Thorax, January 1, 2004; 59(1): 31 - 38. [Abstract] [Full Text] [PDF]

				N. W. Morrell, P. D. Upton, S. Kotecha, A. Huntley, M. H. Yacoub, J. M. Polak, and J. Wharton Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L440 - L448. [Abstract] [Full Text] [PDF]

				H. G Hutchinson, L. Hein, M. Fujinaga, and R. E Pratt Modulation of vascular development and injury by angiotensin II Cardiovasc Res, March 1, 1999; 41(3): 689 - 700. [Abstract] [Full Text] [PDF]

				P Lindahl, L Karlsson, M Hellstrom, S Gebre-Medhin, K Willetts, J. Heath, and C Betsholtz Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development Development, January 10, 1997; 124(20): 3943 - 3953. [Abstract] [PDF]