Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
International Training Program in Geroscience, First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Geroscience. 2022 Apr;44(2):953-981. doi: 10.1007/s11357-022-00519-1. Epub 2022 Feb 5.
Vascular aging has a central role in the pathogenesis of cardiovascular diseases contributing to increased mortality of older adults. There is increasing evidence that, in addition to the documented role of cell-autonomous mechanisms of aging, cell-nonautonomous mechanisms also play a critical role in the regulation of vascular aging processes. Our recent transcriptomic studies (Kiss T. et al. Geroscience. 2020;42(2):727-748) demonstrated that circulating anti-geronic factors from young blood promote vascular rejuvenation in aged mice. The present study was designed to expand upon the results of this study by testing the hypothesis that circulating pro-geronic factors also contribute to the genesis of vascular aging phenotypes. To test this hypothesis, through heterochronic parabiosis, we determined the extent to which shifts in the vascular transcriptome (RNA-seq) are modulated by the old systemic environment. We reanalyzed existing RNA-seq data, comparing the transcriptome in the aorta arch samples isolated from isochronic parabiont aged (20-month-old) C57BL/6 mice [A-(A); parabiosis for 8 weeks] and young isochronic parabiont (6-month-old) mice [Y-(Y)] and also assessing transcriptomic changes in the aortic arch in young (6-month-old) parabiont mice [Y-(A); heterochronic parabiosis for 8 weeks] induced by the presence of old blood derived from aged (20-month-old) parabionts. We identified 528 concordant genes whose expression levels differed in the aged phenotype and were shifted towards the aged phenotype by the presence of old blood in young Y-(A) animals. Among them, the expression of 221 concordant genes was unaffected by the presence of young blood in A-(Y) mice. GO enrichment analysis suggests that old blood-regulated genes may contribute to pathologic vascular remodeling. IPA Upstream Regulator analysis (performed to identify upstream transcriptional regulators that may contribute to the observed transcriptomic changes) suggests that the mechanism of action of pro-geronic factors present in old blood may include inhibition of pathways mediated by SRF (serum response factor), insulin-like growth factor-1 (IGF-1) and VEGF-A. In conclusion, relatively short-term exposure to old blood can accelerate vascular aging processes. Our findings provide additional evidence supporting the significant plasticity of vascular aging and the existence of circulating pro-geronic factors mediating pathological remodeling of the vascular smooth muscle cells and the extracellular matrix.
血管衰老在心血管疾病的发病机制中起着核心作用，导致老年人死亡率增加。越来越多的证据表明，除了已证实的细胞自主衰老机制的作用外，细胞非自主机制也在调节血管衰老过程中起着关键作用。我们最近的转录组学研究（Kiss T. 等人，《老年科学》，2020 年；42（2）：727-748）表明，来自年轻血液的循环抗衰老因子可促进老年小鼠的血管年轻化。本研究旨在通过测试以下假设来扩展该研究的结果，即循环促衰老因子也有助于血管衰老表型的产生。为了验证这一假设，我们通过异时性联体动物实验，确定了血管转录组（RNA-seq）的变化在多大程度上受到老年系统环境的调节。我们重新分析了现有的 RNA-seq 数据，比较了从同时间联体老年（20 月龄）C57BL/6 小鼠（A-（A）；联体 8 周）和年轻同时间联体小鼠（Y-（Y））分离的主动脉弓样本中的转录组，还评估了年轻（6 月龄）联体小鼠（Y-（A）；异时性联体 8 周）中由于来自老年（20 月龄）联体的老年血液的存在而导致的主动脉弓转录组变化。我们确定了 528 个一致基因，其表达水平在老年表型中存在差异，并通过年轻 Y-（A）动物中存在老年血液而向老年表型转移。其中，221 个一致基因的表达在 A-（Y）小鼠中不受年轻血液的影响。GO 富集分析表明，老年血液调控的基因可能有助于病理性血管重塑。IPA 上游调节剂分析（进行该分析以确定可能导致观察到的转录组变化的上游转录调节剂）表明，老年血液中存在的促衰老因子的作用机制可能包括抑制由 SRF（血清反应因子）、胰岛素样生长因子-1（IGF-1）和 VEGF-A 介导的途径。总之，短期接触老年血液可加速血管衰老过程。我们的发现为支持血管衰老的显著可塑性以及存在循环促衰老因子介导血管平滑肌细胞和细胞外基质的病理性重塑提供了额外的证据。
