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. 2009 Apr;296(4):F780-9.
doi: 10.1152/ajprenal.90444.2008. Epub 2009 Jan 7.

Hypertension in mice lacking the CXCR3 chemokine receptor

Hsiang-Hao Hsu  1 , Kerstin Duning, Hans Henning Meyer, Miriam Stölting, Thomas Weide, Stefanie Kreusser, Truc van Le, Craig Gerard, Ralph Telgmann, Stefan-Martin Brand-Herrmann, Hermann Pavenstädt, Martin Johannes Bek
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Free article

Hypertension in mice lacking the CXCR3 chemokine receptor

Hsiang-Hao Hsu et al. Am J Physiol Renal Physiol. 2009 Apr.
Free article

Abstract

The CXC chemokine receptor 3 (CXCR3) has been linked to autoimmune and inflammatory disease, allograft rejection, and ischemic nephropathy. CXCR3 is expressed on endothelial and smooth muscle cells. Although a recent study posited that antagonizing of CXCR3 function may reduce atherosclerosis, the role of CXCR3 in controlling physiological vascular functions remains unclear. This study demonstrates that disruption of CXCR3 leads to elevated mean arterial pressures in anesthetized and conscious mice, respectively. Stimulation of isolated resistance vessels with various vasoconstrictors showed increased contractibility in CXCR3-/- mice in response to angiotensin II (ANG II) and a decreased vasodilatation in response to acetylcholine (ACh). The increased contractibility was related to higher ANG II type 1 receptor (AT1R) expression, whereas the decreased vasodilatation was related to lower M3-ACh receptor expression in the mesenteric arteries of CXCR3-/- mice compared with wild-type mice. The vasodilatatory response to ACh could be antagonized by the nonselective ACh receptor antagonist atropine and the selective M3 receptor antagonist 4-DAMP, but not by M1, M2, and M4 receptor antagonists. Additionally, EMSA studies revealed that transcription factors SP-1 and EGR-1 interact as a complex with the murine AT1R promoter region. Furthermore, we could show increased expression of SP-1 in CXCR3-/- mice indicating an imbalanced SP-1 and EGR-1 complex formation which causes increased AT1R expression and hypertension. The data indicate that CXCR3 receptor is important in vascular contractility and hypertension, possibly through upregulated AT1R expression.

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