title: In vivo estrogen manipulations on coronary capillary network and angiogenic molecule expression in middle-aged female rats.
abstract: 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.
  
  
  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 beta, but not alpha, 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.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sakuma
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
authors.forename: Akira
authors.initials: A
authors.lastname: Kitabatake
mesh_terms: D000367:Age Factors; D043925:Angiogenesis Inducing Agents / Q000096:biosynthesis*; D000818:Animals; D002196:Capillaries / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004958:Estradiol / Q000097:blood; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D043925:Angiogenesis Inducing Agents; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004958:Estradiol; D040262:Receptors, Vascular Endothelial Growth Factor