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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.

Author information

1
1Department of Neurological Sciences, University of Vermont, 149 Beaumont Ave., HSRF 416, Burlington, VT 05405, USA. siu-lung.chan@uvm.edu.

Abstract

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.

KEYWORDS:

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

PMID:
23783073
PMCID:
PMC4046185
DOI:
10.1096/fj.13-230797
[Indexed for MEDLINE]
Free PMC Article
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