Moore Scott M, Zhang Hua, Maeda Nobuyo, Doerschuk Claire M, Faber James E
Department of Cell Biology and Physiology, 6309 MBRB, University of North Carolina, Chapel Hill, NC, 27599-7545, USA.
Angiogenesis. 2015 Jul;18(3):265-81. doi: 10.1007/s10456-015-9465-6. Epub 2015 Apr 11.
Collaterals lessen tissue injury in occlusive disease. However, aging causes progressive decline in their number and smaller diameters in those that remain (collateral rarefaction), beginning at 16 months of age in mice (i.e., middle age), and worse ischemic injury-effects that are accelerated in even 3-month-old eNOS(-/-) mice. These findings have found indirect support in recent human studies.
We sought to determine whether other cardiovascular risk factors (CVRFs) associated with endothelial dysfunction cause collateral rarefaction, investigate possible mechanisms, and test strategies for prevention.
Mice with nine different models of CVRFs of 4-12 months of age were assessed for number and diameter of native collaterals in skeletal muscle and brain and for collateral-dependent perfusion and ischemic injury after arterial occlusion. Hypertension caused collateral rarefaction whose severity increased with duration and level of hypertension, accompanied by greater hindlimb ischemia and cerebral infarct volume. Chronic treatment of wild-type mice with L-N (G)-nitro-arginine methylester caused similar rarefaction and worse ischemic injury which were not prevented by lowering arterial pressure with hydralazine. Metabolic syndrome, hypercholesterolemia, diabetes mellitus, and obesity also caused collateral rarefaction. Neither chronic statin treatment nor exercise training lessened hypertension-induced rarefaction.
Chronic CVRF presence caused collateral rarefaction and worse ischemic injury, even at relatively young ages. Rarefaction was associated with increased proliferation rate of collateral endothelial cells, effects that may promote accelerated endothelial cell senescence.
侧支循环可减轻闭塞性疾病中的组织损伤。然而，衰老会导致其数量逐渐减少，且留存的侧支循环直径变小（侧支循环稀疏），小鼠从16个月龄（即中年）开始出现这种情况，而在3个月龄的eNOS基因敲除小鼠中，缺血性损伤效应更严重且加速出现。这些发现已在近期的人体研究中得到间接支持。
我们试图确定与内皮功能障碍相关的其他心血管危险因素（CVRF）是否会导致侧支循环稀疏，研究可能的机制，并测试预防策略。
对4至12个月龄的9种不同CVRF模型小鼠的骨骼肌和脑中天然侧支循环的数量和直径，以及动脉闭塞后侧支循环依赖的灌注和缺血性损伤进行评估。高血压导致侧支循环稀疏，其严重程度随高血压持续时间和水平增加，同时伴有更严重的后肢缺血和脑梗死体积。用L-N（G）-硝基精氨酸甲酯对野生型小鼠进行慢性治疗会导致类似的稀疏和更严重的缺血性损伤，用肼屈嗪降低动脉压并不能预防这种情况。代谢综合征、高胆固醇血症、糖尿病和肥胖也会导致侧支循环稀疏。慢性他汀类药物治疗和运动训练均不能减轻高血压引起的侧支循环稀疏。
即使在相对年轻的年龄，慢性存在CVRF也会导致侧支循环稀疏和更严重的缺血性损伤。侧支循环稀疏与侧支循环内皮细胞增殖率增加有关，这种效应可能会促进内皮细胞加速衰老。
