Wang Zhenghui, Martorell Belén Cantó, Wälchli Thomas, Vogel Olga, Fischer Jan, Born Walter, Vogel Johannes
Institute of Veterinary Physiology, University of Zürich, Zürich, Switzerland.
Group of CNS Angiogenesis and Neurovascular Link, and Physician-Scientist Program, Swiss Center for Regenerative Medicine, University of Zürich, and Divisions of Neurosurgery and Surgical Research, University Hospital of Zürich, Zürich, Switzerland; Division of Neurosurgery and Laboratory of Molecular Neurooncology, University Hospital Zürich, Zürich, Switzerland; Brain Research Institute, University of Zürich, and Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zürich, Zürich, Switzerland.
PLoS One. 2015 Apr 10;10(4):e0123697. doi: 10.1371/journal.pone.0123697. eCollection 2015.
Cerebral blood flow autoregulation (CA) shifts to higher blood pressures in chronic hypertensive patients, which increases their risk for brain damage. Although cerebral vascular smooth muscle cells express the potent vasodilatatory peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) and their receptors (calcitonin receptor-like receptor (Calclr), receptor-modifying proteins (RAMP) 1 and 2), their contribution to CA during chronic hypertension is poorly understood. Here we report that chronic (10 weeks) hypertensive (one-kidney-one-clip-method) mice overexpressing the Calclr in smooth muscle cells (CLR-tg), which increases the natural sensitivity of the brain vasculature to CGRP and AM show significantly better blood pressure drop-induced cerebrovascular reactivity than wt controls. Compared to sham mice, this was paralleled by increased cerebral CGRP-binding sites (receptor autoradiography), significantly in CLR-tg but not wt mice. AM-binding sites remained unchanged. Whereas hypertension did not alter RAMP-1 expression (droplet digital (dd) PCR) in either mouse line, RAMP-2 expression dropped significantly in both mouse lines by about 65%. Moreover, in wt only Calclr expression was reduced by about 70% parallel to an increase of smooth muscle actin (Acta2) expression. Thus, chronic hypertension induces a stoichiometric shift between CGRP and AM receptors in favor of the CGRP receptor. However, the parallel reduction of Calclr expression observed in wt mice but not CLR-tg mice appears to be a key mechanism in chronic hypertension impairing cerebrovascular reactivity.
慢性高血压患者的脑血流自动调节（CA）会向更高血压水平偏移，这增加了他们脑损伤的风险。尽管脑血管平滑肌细胞表达强效血管舒张肽降钙素基因相关肽（CGRP）和肾上腺髓质素（AM）及其受体（降钙素受体样受体（Calclr）、受体修饰蛋白（RAMP）1和2），但它们在慢性高血压期间对CA的作用却知之甚少。在此我们报告，通过平滑肌细胞中过表达Calclr（CLR转基因）构建的慢性（10周）高血压（单肾单夹法）小鼠，其脑血管对CGRP和AM的天然敏感性增加，与野生型（wt）对照相比，在血压下降诱导的脑血管反应性方面表现显著更好。与假手术小鼠相比，这伴随着脑CGRP结合位点增加（受体放射自显影），在CLR转基因小鼠中显著增加而wt小鼠中未增加。AM结合位点保持不变。虽然高血压在两种小鼠品系中均未改变RAMP - 1表达（液滴数字（dd）PCR），但两种小鼠品系中的RAMP - 2表达均显著下降约65%。此外，仅在wt小鼠中，Calclr表达减少约70%，同时平滑肌肌动蛋白（Acta2）表达增加。因此，慢性高血压诱导CGRP和AM受体之间的化学计量学偏移，有利于CGRP受体。然而，在wt小鼠而非CLR转基因小鼠中观察到的Calclr表达平行降低似乎是慢性高血压损害脑血管反应性的关键机制。
