Dore-Duffy Paula, Wang Sherry, Mehedi Afroza, Katyshev Vladamir, Cleary Kristen, Tapper Alexander, Reynolds Christian, Ding Yuchuan, Zhan Pang, Rafols José, Kreipke Christian W
Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Neurol Res. 2011 Mar;33(2):176-86. doi: 10.1179/016164111X12881719352372.
Endothelin-1 is a 21-amino acid peptide that together with specific receptors, A (ETrA) and B (ETrB) is induced following traumatic brain injury (TBI) and has been closely linked to regulation of cerebral vasospasm, oxidative stress, and hypoperfusion. Specific endothelin receptor antagonists have been shown to ameliorate early evidence of neuronal cell injury, activation of microglial cells, and hypoperfusion following TBI. The exact mechanism involved in TBI-induced hypoperfusion is still unclear; however, it is thought that endothelin-1 engagement of ETrA is primarily responsible for changes in blood flow. In this study we question the role of the microvascular pericyte in endothelin-1-mediated pathophysiology in TBI.
Pericyte expression of endothelin-1, ETrA, and ETrB was examined in primary culture and in sham and impacted rat brain. Adult male rats were also given intracerebroventricular injections of ETrA (BQ-123) before being subjected to TBI using a closed head acceleration impact model.
Primary pericytes express both endothelin-1 and its receptors ETrA and ETrB. Following TBI, the number of alpha-smooth muscle actin (SMA) positive pericytes located in microvessels is significantly increased by 4 hours post-traumatic impact. Increases in pericyte expression of alpha-SMA correlated with evidence of a reduction in both arteriolar and capillary diameter. Capillary endothelin-1, ETrA, and ETrB transcript and protein was also increased. Increased endothelin-1 expression was seen by 2-4 hours post-impact. Upregulation of receptors was observed by 4-8 hours and maximum by 24 hours. ETrA antagonists decreased the number of alpha-SMA(+) pericytes as well as changes in microvascular diameter.
These results suggest that decreased vasoconstriction following TBI may be due to an endothelin-1-induced pericyte-mediated regulation of microvessel blood flow following TBI. Furthermore, results suggest that ETrA antagonists ameliorate trauma induced hypoperfusion, in part, by inhibiting endothelin-1-mediated upregulation of alpha-SMA in pericytes.
内皮素 -1 是一种由 21 个氨基酸组成的肽，在创伤性脑损伤（TBI）后，它与特异性受体 A（ETrA）和 B（ETrB）一起被诱导产生，并且与脑血管痉挛、氧化应激和灌注不足的调节密切相关。已证实特异性内皮素受体拮抗剂可改善 TBI 后神经元细胞损伤、小胶质细胞激活和灌注不足的早期迹象。TBI 诱导的灌注不足的确切机制仍不清楚；然而，据认为内皮素 -1 与 ETrA 的结合主要是导致血流变化的原因。在本研究中，我们探讨了微血管周细胞在 TBI 中内皮素 -1 介导的病理生理学中的作用。
在原代培养以及假手术和撞击后的大鼠脑中检测周细胞内皮素 -1、ETrA 和 ETrB 的表达。成年雄性大鼠在使用闭合性头部加速撞击模型进行 TBI 之前，还接受了脑室内注射 ETrA（BQ - 123）。
原代周细胞表达内皮素 -1 及其受体 ETrA 和 ETrB。TBI 后，创伤后 4 小时位于微血管中的α - 平滑肌肌动蛋白（SMA）阳性周细胞数量显著增加。周细胞α - SMA 表达的增加与小动脉和毛细血管直径减小的证据相关。毛细血管内皮素 -1、ETrA 和 ETrB 的转录本和蛋白也增加。撞击后 2 - 4 小时可见内皮素 -1 表达增加。4 - 8 小时观察到受体上调，24 小时达到最大值。ETrA 拮抗剂减少了α - SMA(+)周细胞的数量以及微血管直径的变化。
这些结果表明，TBI 后血管收缩减少可能是由于内皮素 -1 诱导的周细胞介导的 TBI 后微血管血流调节。此外，结果表明 ETrA 拮抗剂部分地通过抑制内皮素 -1 介导的周细胞中α - SMA 的上调来改善创伤诱导的灌注不足。
