Young Alexander P, Zhu Jiequan, Bagher Amina M, Denovan-Wright Eileen M, Howlett Susan E, Kelly Melanie E M
Department of Pharmacology, Dalhousie University, Halifax, NS, B3H 4R2, Canada.
Department of Pharmacology and Toxicology, King Abdulaziz University, Jeddah, Saudi Arabia.
Geroscience. 2021 Jun;43(3):1447-1463. doi: 10.1007/s11357-020-00309-7. Epub 2021 Jan 5.
The human brain requires adequate cerebral blood flow to meet the high demand for nutrients and to clear waste products. With age, there is a chronic reduction in cerebral blood flow in small resistance arteries that can eventually limit proper brain function. The endothelin system is a key mediator in the regulation of cerebral blood flow, but the contributions of its constituent receptors in the endothelial and vascular smooth muscle layers of cerebral arteries have not been well defined in the context of aging. We isolated posterior cerebral arteries from young and aged Fischer 344 rats, as well as ET receptor knock-out rats and mounted the vessels in plexiglass pressure myograph chambers to measure myogenic tone in response to increasing pressure and targeted pharmacological treatments. We used an ET receptor antagonist (BQ-123), an ET receptor antagonist (BQ-788), endothelin-1, an endothelin-1 synthesis inhibitor (phosphoramidon), and vessel denudation to dissect the roles of each receptor in aging vasculature. Aged rats exhibited a higher myogenic tone than young rats, and the tone was sensitive to the ET antagonist, BQ-123, but insensitive to the ET antagonist, BQ-788. By contrast, the tone in the vessels from young rats was raised by BQ-788 but unaffected by BQ-123. When the endothelial layer that is normally enriched with ET receptors was removed from young vessels, myogenic tone increased. However, denudation of the endothelial layer did not influence vessels from aged animals. This indicated that endothelial ET receptors were not functional in the vessels from aged rats. There was also an increase in ET receptor expression with age, whereas ET receptor expression remained constant between young and aged animals. These results demonstrate that in young vessels, ET receptors maintain a lower myogenic tone, but in aged vessels, a loss of ET receptor activity allows ET receptors in vascular smooth muscle cells to raise myogenic tone. Our findings have potentially important clinical implications for treatments to improve cerebral perfusion in older adults with diseases characterized by reduced cerebral blood flow.
人类大脑需要充足的脑血流量来满足对营养物质的高需求并清除代谢废物。随着年龄增长，小阻力动脉的脑血流量会慢性减少，最终可能限制大脑的正常功能。内皮素系统是调节脑血流量的关键介质，但其在脑动脉内皮和血管平滑肌层中的组成受体在衰老背景下的作用尚未明确。我们从年轻和老年的Fischer 344大鼠以及内皮素受体敲除大鼠中分离出大脑后动脉，并将血管安装在有机玻璃压力肌动描记室中，以测量对压力增加和靶向药物治疗的肌源性张力反应。我们使用内皮素受体拮抗剂（BQ-123）、内皮素受体拮抗剂（BQ-788）、内皮素-1、内皮素-1合成抑制剂（磷酰胺脒）以及血管剥脱术来剖析每个受体在衰老血管系统中的作用。老年大鼠表现出比年轻大鼠更高的肌源性张力，且该张力对内皮素拮抗剂BQ-123敏感，但对内皮素拮抗剂BQ-788不敏感。相比之下，BQ-788可提高年轻大鼠血管的张力，但不受BQ-123影响。当从年轻血管中去除通常富含内皮素受体的内皮层时，肌源性张力增加。然而，内皮层剥脱对老年动物的血管没有影响。这表明老年大鼠血管中的内皮素受体无功能。随着年龄增长，内皮素受体表达也增加，而年轻和老年动物之间内皮素受体表达保持恒定。这些结果表明，在年轻血管中，内皮素受体维持较低的肌源性张力，但在老年血管中，内皮素受体活性丧失使血管平滑肌细胞中的内皮素受体提高肌源性张力。我们的研究结果对于改善患有脑血流量减少相关疾病的老年人脑灌注的治疗具有潜在的重要临床意义。
