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 genderbased 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-␣, 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-␤ 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. (Endocrinology 145: 4330 -4343, 2004)

Association between symptoms of attention-deficit/hyperactivity disorder and bulimic behaviors in a clinical sample of severely obese adolescents

“…Although it has been reported that gonadal hormone metabolism may be involved in the clinical manifestation of ADHD symptoms, these data were obtained in animal models during the development of frontocortical neurons. 22 It is premature to extrapolate the results of these neurobiological studies to human adolescents. Therefore, further studies evaluating the effect of puberty on the expression of ADHD symptoms in obese adolescents are needed.…”

“…Moreover, preliminary evidence from neurobiological studies suggests that hormonal factors may modulate ADHD symptoms. [21][22][23][24] However, the relationship between pubertal stage and severity of ADHD symptoms has not been investigated in obese subjects.…”

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

“…Jesmin and colleagues 27,28 reported that SHRSP rats have reduced regional cerebral blood flow, angiogenic factors, and cerebral microvessel density in the cerebral cortex at 6 weeks of age in comparison with age-matched WKY rats. 28 In our study, vehicle-treated SHRSP rats also demonstrated reduced cerebral microvessel density at 12 weeks of age, the time of occlusion, in comparison with the WKY rats to a degree similar to the previous report. EETs have been shown to induce angiogenesis in several in vivo models and on co-culture of astrocytes and endothelial cells.…”

Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts

“…The samples (20 g of protein) were then subjected to heat denaturation at 96°C for 7 min with Laemmli buffer. Western blot analysis for detection of phosphorylated and nonphosphorylated forms of different target molecules was performed according to the method described in previous studies with minor modification (15,18,25,28,45,52). Briefly, each sample was separated on 10% SDS-polyacrylamide gel and transferred to a polyvinylidene difluoride (Millipore, Billerica, MA) membrane.…”

“…For immunohistochemical determination of target molecules, the tissue sections were exposed to the fluorescent secondary antibody after overnight incubation with each primary antibody, as fully described in our previous reports (24,25). Immunofluorescent images were observed under Laser Scanning Confocal Imaging System (24,25). Phosphorylated eNOS and phosphorylated Akt were purchased from Santa Cruz Biotechnology and Cell Signaling Technology, respectively.…”