Estradiol regulates angiopoietin-1 mRNA expression through estrogen receptor-alpha in a rodent experimental stroke model.
OBJECTIVE
Female, compared with male, animals are protected from cerebral ischemic injury. Physiological concentrations of 17beta-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 microg 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-alpha 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.
Ardelt
Agnieszka A
AA
Department of Neurology, Johns Hopkins Medical Institutions, Baltimore, Md, USA. aardelt1@jhmi.edu
McCullough
Louise D
LD
Korach
Kenneth S
KS
Wang
Michael M
MM
Munzenmaier
Diane H
DH
Hurn
Patricia D
PD
D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000378:metabolism*; D004195:Disease Models, Animal; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D010919:Placebos; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000235:genetics; D015427:Reperfusion Injury; D012260:Ribonucleases / Q000378:metabolism; D020521:Stroke / Q000235:genetics*; D013696:Temperature; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042683:Angiopoietin-1; D047628:Estrogen Receptor alpha; D010919:Placebos; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D012260:Ribonucleases