title: Treatment for cerebral small vessel disease: effect of relaxin on the function and structure of cerebral parenchymal arterioles during hypertension.
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.
authors.affiliation: 1Department of Neurological Sciences, University of Vermont, 149 Beaumont Ave., HSRF 416, Burlington, VT 05405, USA. siu-lung.chan@uvm.edu.
authors.forename: Siu-Lung
authors.initials: SL
authors.lastname: Chan
authors.forename: Julie G
authors.initials: JG
authors.lastname: Sweet
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Cipolla
mesh_terms: D000818:Animals; D001160:Arterioles / Q000502:physiology*; D054022:Cerebrum / Q000098:blood supply*; D005260:Female; D005786:Gene Expression Regulation; D006973:Hypertension / Q000188:drug therapy*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D012065:Relaxin / Q000627:therapeutic use*
chemical_list: D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C033395:relaxin receptors; D012065:Relaxin; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: blood-brain barrier; inward remodeling; matrix metalloproteinase-2; spontaneous hypertensive rats; vascular endothelial growth factor