title: Hypertension in mice lacking the CXCR3 chemokine receptor.
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.
authors.affiliation: Dept. of Internal Medicine, Albert-Schweitzer-Str. 33, D-48149 Münster, Germany.
authors.forename: Hsiang-Hao
authors.initials: HH
authors.lastname: Hsu
authors.forename: Kerstin
authors.initials: K
authors.lastname: Duning
authors.forename: Hans Henning
authors.initials: HH
authors.lastname: Meyer
authors.forename: Miriam
authors.initials: M
authors.lastname: Stölting
authors.forename: Thomas
authors.initials: T
authors.lastname: Weide
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kreusser
authors.forename: Truc
authors.initials: T
authors.lastname: van Le
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: Ralph
authors.initials: R
authors.lastname: Telgmann
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand-Herrmann
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Martin Johannes
authors.initials: MJ
authors.lastname: Bek
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018727:Muscarinic Antagonists / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000172:deficiency* / Q000235:genetics; D012965:Sodium Chloride; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C515188:Cxcr3 protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D018727:Muscarinic Antagonists; D044140:Receptor, Angiotensin, Type 1; D043587:Receptor, Muscarinic M3; D054367:Receptors, CXCR3; D016329:Sp1 Transcription Factor; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D012965:Sodium Chloride