on August 22, 2002
Published online before print August 22, 2002, doi: 10.1161/01.ATV.0000034929.42459.0D
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Submitted on June 2, 2002
Accepted on August 11, 2002
In Vivo Estrogen Manipulations on Coronary Capillary Network and Angiogenic Molecule Expression in Middle-Aged Female Rats
Subrina Jesmin ;
From the Departments of Cardiovascular Medicine (S.J., I.S., A.K.) and Pharmacology (Y.H.), Hokkaido University School of Medicine, Sapporo, Japan.
* To whom correspondence should be addressed. E-mail: sakuichi{at}seagreen.ocn.ne.jp.
Objective—Estrogen replacement therapy (ERT) ameliorates symptoms in postmenopausal women with syndrome X. We hypothesized that estrogen deprivation and replacement may modulate coronary expressions of angiogenic molecules, thereby modifying the coronary capillary network in perimenopausal women.
Methods and Results—Middle-aged (40-week-old) female rats were subjected to sham surgery, ovariectomy, or ovariectomy with ERT. Using immunohistochemical and in situ hybridization techniques, we showed that protein and gene expressions of estrogen receptor ß, but not 
, in coronary vessels were regulated by in vivo estrogen manipulations. Morphometric analysis showed a reduction in total coronary capillary density with decreased arteriolar capillaries after ovariectomy. ERT resulted in normalization of total capillary number with increased venular capillaries. Coronary expressions of vascular endothelial growth factor (VEGF) and its angiogenic receptor (fetal liver kinase-1) were diminished after ovariectomy, and ERT restored it to intact levels. Higher expressions of VEGF and fetal liver kinase-1 in middle-aged compared with young female rats were associated with an accumulation of hypoxia-inducible factor-1 protein, which was highly expressed in middle-aged female rats.
Conclusions—The coronary capillary network in middle-aged women may be regulated by physiological angiogenesis via VEGF, and reduction in coronary VEGF expression by estrogen deficiency could play a role as a molecular pathogenesis in the development of coronary heart disease in postmenopausal women.
Key words: angiogenesis • coronary capillary network • estrogen • vascular endothelial growth factors • middle-aged female rats
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