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FASEB J. 2013 Oct;27(10):3917-27. doi: 10.1096/fj.13-230797. Epub 2013 Jun 19.

Treatment for cerebral small vessel disease: effect of relaxin on the function and structure of cerebral parenchymal arterioles during hypertension.

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1Department of Neurological Sciences, University of Vermont, 149 Beaumont Ave., HSRF 416, Burlington, VT 05405, USA.


We investigated the effect of hypertension on the function and structure of cerebral parenchymal arterioles (PAs), a major target of cerebral small vessel disease (SVD), and determined whether relaxin is a treatment for SVD during hypertension. PAs were isolated from 18-wk-old female normotensive Wistar-Kyoto (WKY) rats, spontaneous hypertensive rats (SHRs), and SHRs treated with human relaxin 2 for 14 d (4 μg/h; n=8/group) and studied using a pressurized arteriograph system. Hypertension reduced PA inner diameter (58±3 vs. 49±3 μm at 60 mmHg in WKY rats, P<0.05), suggesting inward remodeling that was reversed by relaxin (56±4 μm, P<0.05). Relaxin also increased PA distensibility in SHRs (34±2 vs. 10±2% in SHRs, P<0.05). Relaxin was detected in cerebrospinal fluid (110±30 pg/ml) after systemic administration, suggesting that it crosses the blood-brain barrier (BBB). Relaxin receptors (RXFP1/2) were not detected in cerebral vasculature, but relaxin increased vascular endothelial growth factor (VEGF) and matrix metalloproteinase 2 (MMP-2) expression in brain cortex. Inhibition of VEGF receptor tyrosine kinase (axitinib, 4 mg/kg/d, 14 d) had no effect on increased distensibility with relaxin, but caused outward hypertrophic remodeling of PAs from SHRs. These results suggest that relaxin crosses the BBB and activates MMP-2 in brain cortex, which may interact with PAs to increase distensibility. VEGF appears to be involved in remodeling of PAs, but not relaxin-induced increased distensibility.


blood-brain barrier; inward remodeling; matrix metalloproteinase-2; spontaneous hypertensive rats; vascular endothelial growth factor

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