title: Gonadal hormones and frontocortical expression of vascular endothelial growth factor in male stroke-prone, spontaneously hypertensive rats, a model for attention-deficit/hyperactivity disorder.
abstract: Attention-deficit/hyperactivity disorder (AD/HD) is a common pediatric behavioral disorder associated, in part, with male preponderance and reduced regional cerebral blood flow (rCBF). However, mechanism(s) underlying male preponderance and reduced rCBF in AD/HD are unclear. The present study profiles the expression of angiogenic and hormonal factors likely to underlie these symptoms using a recently characterized AD/HD animal model, juvenile male stroke-prone spontaneously hypertensive rats (SHRSP). Because vascular endothelial growth factor (VEGF) signaling cascade and gonadal steroids are key regulators of angiogenesis and gender-based behavior, respectively, we profiled their patterns of expression in the frontal cortex of SHRSP to elucidate their roles in the genesis of AD/HD male preponderance and rCBF. Interestingly, levels of VEGF, VEGF receptors (KDR, Flt-1), endothelial nitric oxide synthase, phosphorylated Akt (pAkt), estrogen receptor-alpha, aromatase, and capillary density in sham-operated SHRSP were remarkably down-regulated, whereas androgen receptor levels were up-regulated, compared with age-matched genetic control, Wistar-Kyoto rats. Castration, estrogen, and androgen receptor antagonist (flutamide) counteracted these effects. Dihydrotestosterone, but not testosterone, reversed the beneficiary effects of castration. Estrogen receptor-beta levels remained unchanged in all groups examined. We postulate that changes in androgen metabolism that tend to up-regulate local dihydrotestosterone concentration and diminish estrogen synthesis, in the frontal cortex of juvenile male SHRSP, may lower levels and/or activity of VEGF and its signaling cascade and, subsequently, reduce rCBF. These findings could, in part, help explain the pathogenesis of reduced rCBF and male preponderance in AD/HD.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sakuma
authors.forename: Chishimba N
authors.initials: CN
authors.lastname: Mowa
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Ueno
authors.forename: Taku
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Akira
authors.initials: A
authors.lastname: Kitabatake
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics; D001289:Attention Deficit Disorder with Hyperactivity / Q000503:physiopathology*; D002196:Capillaries / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000502:physiology; D013196:Dihydrotestosterone / Q000097:blood; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000097:blood; D005625:Frontal Lobe / Q000098:blood supply*; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011944:Receptors, Androgen / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000503:physiopathology; D013739:Testosterone / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D013196:Dihydrotestosterone; D009569:Nitric Oxide; D013739:Testosterone; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001141:Aromatase; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt