Miyashiro J K, Poppa V, Berk B C
Department of Medicine, University of Washington, Seattle 98195, USA.
Circ Res. 1997 Sep;81(3):311-9. doi: 10.1161/01.res.81.3.311.
Vascular remodeling is regulated by a combination of hemodynamic, environmental, and genetic factors and may be influenced by age. To evaluate age-dependent remodeling in rats, we developed and used a quantitative highly reproducible model of carotid flow alteration. Fourteen juvenile (99+/-3 g) and 9 adult (199+/-5 g) male inbred Fischer rats underwent ligation of the left internal and external carotid arteries under anesthesia. Left common carotid blood flow immediately decreased by approximately 93%, whereas flow in the contralateral carotid increased by approximately 46%. After 4 weeks, the left carotid outer diameter (OD) significantly decreased in both juvenile and adult rats (as measured in vivo and by histological morphometry) compared with sham-operated rats. Changes in shear stress acutely mirrored the changes in blood flow. OD increased and shear stress returned to initial values after chronic exposure to increased flow in juvenile but not adult rats. To develop a simple quantitative index of remodeling that would not require killing the animals, we measured the OD in vivo and compared the ratio of right to left OD (OD ratio [ODR]) between groups. The initial ODR for all groups was approximately 1.0. After 4 weeks of altered flow, the ODR was significantly greater in juvenile than in adult rats (1.48+/-0.05 versus 1.29+/-0.04, respectively; P=.030), indicating that juvenile rats experienced more extensive remodeling than did the adult rats. We also found that unilateral carotid ligation caused a left versus right difference in endothelial NO synthase protein levels after 4 weeks that was not present in the sham-operated animals. Thus, the model described here shows that flow-induced vascular remodeling is dependent on age and supports the hypothesis that the driving force for remodeling involves shear stress and possibly NO. Because the model is quantitative, it allows dissection of the genetic factors that regulate remodeling in inbred rat strains.
血管重塑受血流动力学、环境和遗传因素共同调节，且可能受年龄影响。为评估大鼠年龄依赖性重塑，我们开发并使用了一种定量且高度可重复的颈动脉血流改变模型。14只幼年（99±3克）和9只成年（199±5克）雄性近交系Fischer大鼠在麻醉下接受左颈内动脉和颈外动脉结扎。左颈总动脉血流立即减少约93%，而对侧颈动脉血流增加约46%。4周后，与假手术大鼠相比，幼年和成年大鼠的左颈动脉外径（OD）均显著减小（通过体内测量和组织形态学测量）。剪切应力的变化与血流变化即刻呈现出镜像关系。在幼年大鼠而非成年大鼠中，长期暴露于增加的血流后，外径增加且剪切应力恢复到初始值。为建立一个无需处死动物的简单重塑定量指标，我们在体内测量外径并比较了各组左右外径之比（外径比[ODR]）。所有组的初始ODR约为1.0。血流改变4周后，幼年大鼠的ODR显著高于成年大鼠（分别为1.48±0.05和1.29±0.04；P = 0.030），表明幼年大鼠经历的重塑比成年大鼠更广泛。我们还发现，单侧颈动脉结扎4周后，假手术动物不存在左、右内皮型一氧化氮合酶蛋白水平差异。因此，本文所述模型表明血流诱导的血管重塑依赖于年龄，并支持重塑驱动力涉及剪切应力且可能涉及一氧化氮的假说。由于该模型是定量的，它允许剖析调节近交系大鼠品系重塑的遗传因素。
