Department of Molecular Medicine, Faculty of Health Sciences (K.B.C., Ş.Ü., L.H., A.S., K.R., P.B.L.H., B.L.J., M.B., G.L.S.), University of Southern Denmark, Odense.
Department of Biochemistry and Molecular Biology (M.F.E.), University of Southern Denmark, Odense.
Hypertension. 2024 Jun;81(6):1308-1319. doi: 10.1161/HYPERTENSIONAHA.123.22283. Epub 2024 Apr 2.
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.
Mesenteric arteries were isolated from old (20-23 months) littermate and 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 and 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.
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 mice relative to mice. Increased efficacy of vasoconstrictors (phenylephrine, thromboxane) and reduced stiffness were observed in Ang II-treated mouse mesenteric arteries in ex vivo myography recordings.
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.
阻力动脉的异常可能在衰老和高血压的病理生理学中起重要作用。以前观察到血管细胞外基质蛋白 MFAP4（微纤维相关蛋白 4）的缺乏可防止动脉重塑异常。我们假设 MFAP4 缺乏会减少年龄和高血压依赖性细胞外基质组成和僵硬的动脉变化。
从小鼠分离出肠系膜动脉，使用双光子激发显微镜成像技术来定量血管壁中弹性蛋白和胶原蛋白的体积和尺寸。将 10 周龄的同窝 和 小鼠进行 20 天的持续 Ang II（血管紧张素 II）输注，并通过有创血压测量监测高血压。使用线或压力肌描法监测动脉僵硬、血管收缩剂的反应和肌源性张力。通过 Western blot 评估胶原蛋白含量。
MFAP4 缺乏显著增加了老年肠系膜动脉中的胶原蛋白体积和弹性蛋白碎片化，而不影响动脉僵硬。MFAP4 缺乏的小鼠在 Ang II 诱导的高血压中舒张压降低。MFAP4 缺乏对肠系膜动脉结构重塑或肌源性张力没有明显影响，尽管与 小鼠相比，高血压 小鼠的肠系膜动脉中胶原蛋白含量有增加的趋势。在离体肌描记录中，观察到 Ang II 处理的 小鼠肠系膜动脉中血管收缩剂（苯肾上腺素、血栓素）的功效增加和僵硬降低。
MFAP4 缺乏降低了衰老阻力动脉中的弹性蛋白/胶原蛋白比值，而不影响动脉僵硬。相比之下，MFAP4 缺乏降低了阻力动脉的僵硬，并改善了 Ang II 诱导的高血压。
