BACKGROUND:Abnormalities of resistance arteries may play essential roles in the pathophysiology of aging and hypertension. Deficiency of the vascular extracellular matrix protein MFAP4 (microfibrillar-associated protein 4) has previously been observed as protective against aberrant arterial remodeling. We hypothesized that MFAP4-deficiency would reduce age- and hypertension-dependent arterial changes in extracellular matrix composition and stiffening.METHODS:Mesenteric arteries were isolated from old (20–23 months) littermate Mfap4^+/+ and Mfap4^−/− mice, and 2-photon excitation microscopy imaging was used to quantify elastin and collagen volumes and dimensions in the vascular wall.Ten-week-old littermate Mfap4^+/+ and Mfap4^−/− mice were subjected to 20 days of continuous Ang II (angiotensin II) infusion and hypertension was monitored using invasive blood pressure measurements. Arterial stiffness, responses to vascular constrictors, and myogenic tone were monitored using wire- or pressure myography. Collagen contents were assessed by Western blotting.RESULTS:MFAP4 deficiency significantly increased collagen volume and elastin fragmentation in aged mesenteric arteries without affecting arterial stiffness. MFAP4-deficient mice exhibited reduced diastolic pressure in Ang II-induced hypertension. There was no significant effect of MFAP4-deficiency on mesenteric artery structural remodeling or myogenic tone, although collagen content in mesenteric arteries was tendentially increased in hypertensive Mfap4^+/+ mice relative to Mfap4^−/− mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated Mfap4^−/− mouse mesenteric arteries in ex vivo myography recordings.CONCLUSIONS:MFAP4 deficiency reduces the elastin/collagen ratio in the aging resistance artery without affecting arterial stiffness. In contrast, MFAP4-deficiency reduces the stiffness of resistance arteries and ameliorates Ang II-induced hypertension.

中文翻译：

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MFAP4 缺乏会加剧年龄引起的阻力动脉结构变化，同时改善高血压


背景：阻力动脉异常可能在衰老和高血压的病理生理学中发挥重要作用。先前观察到血管细胞外基质蛋白 MFAP4（微纤维相关蛋白 4）的缺乏可以预防异常动脉重塑。我们假设 MFAP4 缺乏会减少细胞外基质组成和僵化的年龄和高血压依赖性动脉变化。方法：从年老（20-23 个月）同窝Mfap4 ^+/+和Mfap4 ^−/−小鼠中分离肠系膜动脉，并使用 2 光子激发显微镜成像来量化血管壁中弹性蛋白和胶原蛋白的体积和尺寸。十周大的同窝Mfap4 ^+/+和Mfap4 ^−/−小鼠接受 20 天的连续 Ang II（血管紧张素 II）治疗使用有创血压测量来监测输液和高血压。使用线或压力肌动描记术监测动脉僵硬度、对血管收缩器的反应和肌原性张力。通过蛋白质印迹法评估胶原含量。结果：MFAP4 缺乏显着增加了老化肠系膜动脉中的胶原体积和弹性蛋白碎片，而不影响动脉硬度。 MFAP4 缺陷小鼠在 Ang II 诱导的高血压中表现出舒张压降低。 MFAP4缺陷对肠系膜动脉结构重塑或肌原性张力没有显着影响，尽管相对于Mfap4 ^-/−小鼠，高血压Mfap4 ^+/+小鼠肠系膜动脉中的胶原蛋白含量倾向于增加。在离体肌电图记录中，在 Ang II 治疗的Mfap4 ^−/−小鼠肠系膜动脉中观察到血管收缩剂（去氧肾上腺素、血栓素）功效增强，硬度降低。结论：MFAP4 缺乏降低了抗衰老动脉中的弹性蛋白/胶原蛋白比率，但不影响动脉刚性。相反，MFAP4 缺乏会降低阻力动脉的硬度并改善 Ang II 诱导的高血压。