Published Online
on January 6, 2005

A more recent version of this article appeared on February 1, 2005

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Submitted on August 11, 2004
Revised on October 26, 2004
Accepted on November 15, 2004

Estradiol Regulates Angiopoietin-1 mRNA Expression Through Estrogen Receptor- in a Rodent Experimental Stroke Model

Agnieszka A. Ardelt MD, PhD^*; Louise D. McCullough MD, PhD; Kenneth S. Korach PhD; Michael M. Wang MD, PhD; Diane H. Munzenmaier PhD; and Patricia D. Hurn PhD

From the Departments of Neurology (A.A.A., L.D.M., M.M.W.) and Anesthesiology and Critical Care Medicine (A.A.A., P.D.H.), Johns Hopkins Medical Institutions, Baltimore, Md; National Institutes of Health (K.S.K.), Bethesda, Md; and Department of Physiology (D.H.M.), Medical College of Wisconsin, Milwaukee.

^* To whom correspondence should be addressed. E-mail: aardelt1{at}jhmi.edu.

Background and Purpose--Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17-estradiol (E2) reduce damage in experimental stroke. E2 augments angiogenesis in reproductive organs and noncerebral vascular beds. We hypothesized that E2 protects brain in stroke through modulation of angiogenesis. We quantified molecular markers of angiogenesis and capillary density before and after unilateral middle cerebral artery occlusion (MCAO).

Methods--Female animals were ovariectomized, treated with 25 µg E2 or placebo implants, and subjected to 2-hour MCAO and 22 hours of reperfusion. Brain angiopoietin-1 (Ang-1), Ang-2, Tie-1, Tie-2, vascular endothelial growth factor (VEGF), VEGF R1, and VEGF R2 mRNA levels were determined by RNAse protection assays, and CD31-positive vessels were counted.

Results--E2, but not ischemia, upregulated cerebral Ang-1 mRNA by 49%. Capillary density was higher in the brains of E2-treated animals. In estrogen receptor- knockout (ERKO) mice, E2-mediated induction of Ang-1 mRNA was absent relative to wild-type littermates.

Conclusions--These results suggest that E2 increases Ang-1 and enhances capillary density in brain under basal conditions, priming the MCA territory for survival after experimental focal ischemia.

Key words: angiogenesis • cerebrovascular accident • endothelial growth factors

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