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

*Department of Neurological Sciences, †Department of Obstetrics, Gynecology, and Reproductive Sciences, and ‡Department of Pharmacology, University of Vermont, Burlington, Vermont, USA.
The FASEB Journal (Impact Factor: 5.04). 06/2013; 27(10). DOI: 10.1096/fj.13-230797
Source: PubMed


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.-Chan, S.-L., Sweet, J. G., Cipolla, M. J. Treatment for cerebral small vessel disease: effect of relaxin on the function and structure of cerebral parenchymal arterioles during hypertension.

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Available from: Siu-Lung Chan, Nov 12, 2014
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    • "Interestingly, responses to the opener of IKCa and SKCa channels, NS309, was not affected 3 hours after serelaxin injection, suggesting that the augmentation of EDH‐type relaxation involved a signaling mechanism through the BK receptor, rather than activity of the IKCa and SKCa channels. This phenomenon is also reported in a recent study of SHR rats,44 where long‐term relaxin treatment had minimal effect in improving NS309 responses in hypertensive parenchymal arterioles. EDH is an important vasodilator mechanism in small arteries and arterioles and may be an additional mechanism by which relaxin reduces peripheral vascular resistance. "
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