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

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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 C57B1/6 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 C57B1/6 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 C57B1/6 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.

Original languageEnglish (US)
Pages (from-to)596-604
Number of pages9
JournalCirculation research
Issue number6
StatePublished - Sep 16 2005


  • Elastin
  • Fibulin-5
  • Hypoxia
  • Mouse
  • Pulmonary hypertension
  • S100 proteins
  • Smooth muscle cells
  • Vascular disease
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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