Department of Physiology and Pharmacology, Robarts Research Institute, The University of Western Ontario, London, Ontario Canada.
Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1731-7. doi: 10.1152/ajpregu.00274.2011. Epub 2011 Sep 7.
This study examined perturbed aortic development and subsequent wall stiffening as a link to later cardiovascular disease. Placental insufficiency was induced in pregnant guinea pigs at midgestation by uterine artery ligation. Near term, fetuses were killed and defined as normal birth weight (NBW), low birth weight (LBW), and intrauterine growth restricted (IUGR). Offspring were classified according to birth weight and killed in adulthood. Collagen and elastin content of aortas were analyzed using Sirius red and orcein staining, respectively. Immunofluorescence was used for detection of α-actin and nonmuscle myosin heavy chain (MHC-B), a marker of synthetic-type vascular smooth muscle cells (VSMCs). Ex vivo generation of length-tension curves was performed with aortic rings from adult offspring. Relative elastic fiber content was decreased by 10% in LBW and 14% in IUGR compared with NBW fetuses. In adulthood, relative elastic fiber content was 51% lower in LBW vs. NBW, and the number of elastic laminae adjusted for wall thickness was 25% lower in LBW (P < 0.01). The percent area stained for MHC-B was sixfold higher in LBW vs. NBW fetuses (P < 0.0001) and threefold higher in LBW vs. NBW adult offspring (P < 0.05). The increase in MHC-B in LBW offspring concurred with a 41% increase in total collagen content and a 33 and 56% increase in relative and total α-actin content, respectively (P < 0.05). Thus aortic wall stiffening in adulthood can be traced to altered matrix composition established under suboptimal intrauterine conditions that is amplified postnatally by the activity of synthetic VSMCs.
本研究探讨了动脉发育紊乱和随后的壁僵硬度作为与心血管疾病发生的关联。在妊娠中期通过子宫动脉结扎诱导怀孕豚鼠发生胎盘功能不全。接近足月时，处死胎儿并定义为正常出生体重（NBW）、低出生体重（LBW）和宫内生长受限（IUGR）。根据出生体重对后代进行分类，并在成年后处死。使用天狼星红和地衣红染色分别分析主动脉的胶原和弹性蛋白含量。免疫荧光用于检测α-肌动蛋白和非肌肉肌球蛋白重链（MHC-B），这是合成型血管平滑肌细胞（VSMC）的标志物。使用成年后代的主动脉环进行体外张力-长度曲线生成。LBW 和 IUGR 组的相对弹性纤维含量比 NBW 组分别降低了 10%和 14%。在成年时，LBW 组与 NBW 组相比，相对弹性纤维含量低 51%，并且 LBW 组的弹性层厚度调整后的弹性层数量低 25%（P<0.01）。MHC-B 染色面积百分比在 LBW 组比 NBW 组高 6 倍（P<0.0001），LBW 组比 NBW 组高 3 倍（P<0.05）。LBW 后代中 MHC-B 的增加与总胶原蛋白含量增加 41%、相对和总α-肌动蛋白含量分别增加 33%和 56%相一致（P<0.05）。因此，成年时主动脉壁僵硬度可追溯到宫内环境不理想时建立的基质组成改变，这种改变在出生后被合成型 VSMC 的活性放大。
