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(Circulation Research. 2005;97:596.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Increased Fibulin-5 and Elastin in S100A4/Mts1 Mice With Pulmonary Hypertension

Sandra L. Merklinger, Roger A. Wagner, Edda Spiekerkoetter, Aleksander Hinek, Russell H. Knutsen, M. Golam Kabir, Kavin Desai, Shelby Hacker, Lingli Wang, Gordon M. Cann, Noona S. Ambartsumian, Eugene Lukanidin, Daniel Bernstein, Mansoor Husain, Robert P. Mecham, Barry Starcher, Hiromi Yanagisawa, Marlene Rabinovitch

From the Departments of Pediatrics (S.L.M., E.S., K.D., L.W., G.M.C., D.B., M.R.) and Medicine (R.A.W.), Stanford University School of Medicine, Calif; the Cardiovascular Research Program (A.H.), The Hospital for Sick Children, and the Department of Laboratory Medicine and Pathobiology and Center for Cardiovascular Research (M.G.K., M.H.), The Toronto Hospital Network, Division of Cardiology, Department of Medicine, University of Toronto, Canada; the Department of Medicine (R.H.K., R.P.M.), Washington University School of Medicine, St. Louis, Mo; the Department of Molecular Biology (S.H., H.Y.), University of Texas Southwestern Medical Center at Dallas; the Department of Molecular Cancer (N.S.A., E.L.), Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark; and the Department of Biomedical Research (B.S.), University of Texas Health Science Center at Tyler.

Correspondence to Dr Marlene Rabinovitch, The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, CCSR Bldg, Room 2245a, 269 Campus Dr, Stanford, CA 94305-5162. E-mail marlener{at}stanford.edu

Transgenic mice overexpressing the calcium binding protein, S100A4/Mts1, occasionally develop severe pulmonary vascular obstructive disease. To understand what underlies this propensity, we compared the pulmonary vascular hemodynamic and structural features of S100A4/Mts1 with control C57Bl/6 mice at baseline, following a 2-week exposure to chronic hypoxia, and after 1 and 3 months "recovery" in room air. S100A4/Mts1 mice had greater right ventricular systolic pressure and right ventricular hypertrophy at baseline, which increased further with chronic hypoxia and was sustained after 3 months "recovery" in room air. These findings correlated with a heightened response to acute hypoxia and failure to vasodilate with nitric oxide or oxygen. S100A4/Mts1 mice, when compared with C57Bl/6 mice, also had impaired cardiac function judged by reduced ventricular elastance and decreased cardiac output. Despite higher right ventricular systolic pressures with chronic hypoxia, S100A4/Mts1 mice did not develop more severe PVD, but in contrast to C57Bl/6 mice, these features did not regress on return to room air. Microarray analysis of lung tissue identified a number of genes differentially upregulated in S100A4/Mts1 versus control mice. One of these, fibulin-5, is a matrix component necessary for normal elastin fiber assembly. Fibulin-5 was localized to pulmonary arteries and associated with thickened elastic laminae. This feature could underlie attenuation of pulmonary vascular changes in response to elevated pressure, as well as impaired reversibility.

Key Words: elastin • fibulin-5 • hypoxia • mouse • pulmonary hypertension • smooth muscle cells • S100 proteins • vascular smooth muscle cells • vascular disease

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