Antagonism Of Endothelin Action Normalizes Altered Levels Of VEGF And Its Signaling In The Brain Of Stroke-Prone Spontaneously Hypertensive Rat

ASU Author/Contributor (non-ASU co-authors, if there are any, appear on document)
Dr.. Chishimba Nathan Mowa, Associate Professor (Creator)
Appalachian State University (ASU )
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Abstract: Stroke-prone spontaneously hypertensive rats (SHRSP) often suffer from spontaneous stroke, in part, due to abnormalities in the cerebrovasculature. Here, we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age-dependent stages of hypertension. The profile of VEGF and its receptor, Flk-1, was dependent on age and stage of hypertension (i.e., down regulated at pre-hypertensive and malignant hypertensive stages, but up regulated at typical hypertensive stage), while that of its downstream components, pAkt and eNOS, were down regulated in a time-dependent manner in the frontal cortex of SHRSP compared to age-matched genetic control, normotensive WKY rats. On the other hand, the expression of endothelin-1 and its type A receptor (endothelin ETA receptor) were up regulated, depending on age and stage of hypertension. In contrast, levels of endothelin type B receptor were down regulated. The regional cerebral blood flow decreased during the development of malignant hypertension. Thus, subsequent experiments were designed to investigate whether endothelin-1 receptor antagonism, using endothelin-A/-B dual receptor antagonist SB209670, could normalize the molecular profile of these factors in SHRSP brain. Interestingly, blockage of endothelin-1 receptor restored to normal, levels of cerebral endothelin-1, endothelin ETA receptor and endothelin ETB receptor; VEGF and Flk-1; endothelial nitric oxide synthase (eNOS) and pAkt, in SHRSP, compared to age-matched WKY. Endothelin receptor blocker might be important to prevent the progression in the defect in VEGF and its angiogenic signaling cascade in the pathogenesis of hypertension-induced vascular remodeling in frontal cortex of SHRSP rats.

Additional Information

Subrina Jesmin , Seiji Maeda, Chishimba N. Mowa, Sohel Zaedi, Hiroko Togashi, Shamsul H. Prodhan, Taku Yamaguchi, Mitsuhiro Yoshioka, Ichiro Sakuma, Takashi Miyauchi &Norihiro Kato (2007) "Antagonism Of Endothelin Action Normalizes Altered Levels Of VEGF And Its Signaling In The Brain Of Stroke-Prone Spontaneously Hypertensive Rat" European Journal of Pharmacology #574 pp.158-171 Version of Record Available @ (doi:10.1016/j.ejphar.2007.07.023)
Language: English
Date: 2007
SHRSP, brain, VEGF, Endothelin, Remodeling

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