Isenberg Jeff S, Qin Yan, Maxhimer Justin B, Sipes John M, Despres Daryl, Schnermann Jurgen, Frazier William A, Roberts David D
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, United States.
Matrix Biol. 2009 Mar;28(2):110-9. doi: 10.1016/j.matbio.2009.01.002. Epub 2009 Jan 21.
Nitric oxide (NO) locally regulates vascular resistance and blood pressure by modulating blood vessel tone. Thrombospondin-1 signaling via its receptor CD47 locally limits the ability of NO to relax vascular smooth muscle cells and increase regional blood flow in ischemic tissues. To determine whether thrombospondin-1 plays a broader role in central cardiovascular physiology, we examined vasoactive stress responses in mice lacking thrombospondin-1 or CD47. Mice lacking thrombospondin-1 exhibit activity-associated increases in heart rate, central diastolic and mean arterial blood pressure and a constant decrease in pulse pressure. CD47-deficient mice have normal central pulse pressure but elevated resting peripheral blood pressure. Both null mice show exaggerated decreases in peripheral blood pressure and increased cardiac output and ejection fraction in response to NO. Autonomic blockade also induces exaggerated hypotensive responses in awake thrombospondin-1 null and CD47 null mice. Both null mice exhibit a greater hypotensive response to isoflurane, and autonomic blockage under isoflurane anesthesia leads to premature death of thrombospondin-1 null mice. Conversely, the hypertensive response to epinephrine is attenuated in thrombospondin-1 null mice. Thus, the matricellular protein thrombospondin-1 and its receptor CD47 serve as acute physiological regulators of blood pressure and exert a vasopressor activity to maintain global hemodynamics under stress.
一氧化氮（NO）通过调节血管张力局部调节血管阻力和血压。血小板反应蛋白-1通过其受体CD47发出的信号在局部限制了NO舒张血管平滑肌细胞及增加缺血组织局部血流量的能力。为了确定血小板反应蛋白-1在中枢心血管生理学中是否发挥更广泛的作用，我们检测了缺乏血小板反应蛋白-1或CD47的小鼠的血管活性应激反应。缺乏血小板反应蛋白-1的小鼠在活动时心率、中心舒张压和平均动脉血压升高，脉压持续降低。缺乏CD47的小鼠中心脉压正常，但静息外周血压升高。两种基因敲除小鼠对外周血压的降低反应均增强，对NO的反应中心输出量和射血分数增加。自主神经阻滞在清醒的血小板反应蛋白-1基因敲除和CD47基因敲除小鼠中也会引起过度的降压反应。两种基因敲除小鼠对异氟烷的降压反应均增强，异氟烷麻醉下的自主神经阻滞会导致血小板反应蛋白-1基因敲除小鼠过早死亡。相反，血小板反应蛋白-1基因敲除小鼠对肾上腺素的升压反应减弱。因此，基质细胞蛋白血小板反应蛋白-1及其受体CD47作为血压的急性生理调节因子，在应激状态下发挥血管升压活性以维持整体血流动力学。
