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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/F780    most recent 90444.2008v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hsu, H.-H. Articles by Bek, M. J. Search for Related Content PubMed PubMed Citation Articles by Hsu, H.-H. Articles by Bek, M. J.

Hypertension in mice lacking the CXCR3 chemokine receptor

¹Department of Medicine, Division of Nephrology and General Medicine, University Clinic of Münster, Münster; ³Leibniz-Institute for Arteriosclerosis Research, Department of Molecular Genetics of Cardiovascular Disease, Münster, Germany; ²Department of Medicine, Pulmonary Division, Harvard Medical School, Boston, Massachusetts; and ⁴Kidney Institute and Department of Nephrology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan

Submitted 30 July 2008 ; accepted in final form 5 January 2009

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.

angiotensin II type 1 receptor; acetylcholine receptor; CXCR3 knockout mice; EMSA; transcription factors; vascular contractility