1Department of Neurological Sciences, University of Vermont, 149 Beaumont Ave., HSRF 416, Burlington, VT 05405, USA.
FASEB J. 2013 Oct;27(10):3917-27. doi: 10.1096/fj.13-230797. Epub 2013 Jun 19.
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.
我们研究了高血压对脑实质小动脉（PA）功能和结构的影响，PA 是脑小血管病（SVD）的主要靶点，并确定松弛素是否是高血压期间 SVD 的治疗方法。将 PA 从 18 周龄的雌性正常血压 Wistar-Kyoto（WKY）大鼠、自发性高血压大鼠（SHR）以及接受人松弛素 2 治疗 14 天（4μg/h；n=8/组）的 SHR 中分离出来，并使用加压血管造影系统进行研究。高血压降低了 PA 内直径（60mmHg 时，WKY 大鼠为 58±3μm，P<0.05），提示松弛素逆转了内向重塑（56±4μm，P<0.05）。松弛素还增加了 SHR 的 PA 可扩展性（34±2%对 SHR 的 10±2%，P<0.05）。系统给药后在脑脊液中检测到松弛素（110±30pg/ml），表明它穿过血脑屏障（BBB）。在脑血管中未检测到松弛素受体（RXFP1/2），但松弛素增加了大脑皮质中的血管内皮生长因子（VEGF）和基质金属蛋白酶 2（MMP-2）表达。VEGF 受体酪氨酸激酶抑制剂（axitinib，4mg/kg/d，14d）对松弛素引起的可扩展性增加没有影响，但导致 SHR 的 PA 发生外向肥大重塑。这些结果表明，松弛素穿过 BBB 并激活大脑皮质中的 MMP-2，这可能与 PA 相互作用以增加可扩展性。VEGF 似乎参与了 PA 的重塑，但不参与松弛素诱导的可扩展性增加。
