This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jesmin, S. Articles by Kitabatake, A. Search for Related Content PubMed PubMed Citation Articles by Jesmin, S. Articles by Kitabatake, A.

Gonadal Hormones and Frontocortical Expression of Vascular Endothelial Growth Factor in Male Stroke-Prone, Spontaneously Hypertensive Rats, a Model for Attention-Deficit/Hyperactivity Disorder

Departments of Cardiovascular Medicine and Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan; and Department of Neurobiology, Northeast Ohio Universities, College of Medicine, Rootstown, Ohio 44272-0095

Address all correspondence and requests for reprints to: Ichiro Sakuma, M.D., Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. E-mail: sakuichi{at}seagreen.ocn.ne.jp.

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-, 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-ß 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.

This article has been cited by other articles:

				A. N. Simpkins, R. D. Rudic, D. A. Schreihofer, S. Roy, M. Manhiani, H.-J. Tsai, B. D. Hammock, and J. D. Imig Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection Am. J. Pathol., June 1, 2009; 174(6): 2086 - 2095. [Abstract] [Full Text] [PDF]

				S. Jesmin, S. Zaedi, N. Shimojo, M. Iemitsu, K. Masuzawa, N. Yamaguchi, C. N. Mowa, S. Maeda, Y. Hattori, and T. Miyauchi Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1030 - E1040. [Abstract] [Full Text] [PDF]