Endothelial Progenitor Cell Senescence as a Contributing Cause of Declining Angiogenesis
Angiogenesis is the process of building new blood vessels in response to circumstances, such as a relative lack of oxygenation in tissues, or repair of injury. It is quite complicated, involving several distinct stages and the interactions of a variety of different cell populations. Angiogenesis declines with age, particularly in the context of maintaining capillaries. The density of capillary networks is reduced with age, and this may be quite influential in the aging of energy-hungry issues such as the brain and muscles. It isn't just a reduction in delivery of nutrients and oxygen. Loss of microvascular blood flow through tissues is likely also disruptive to the regulation of blood pressure, a factor contributing to the development of hypertension.
Which of the mechanisms of aging contribute to the loss of angiogenesis with age? Endothelial progenitor cells are one of the cell populations involved in angiogensis. In today's open access paper, the authors discuss cellular senescence in this population, and its negative effects on the capacity for angiogenesis, through the lens of microRNA regulation of these processes. Senescent cells grow in number with advancing age, in cell populations throughout the body. Their presence alters the cellular environment for the worse, generating inflammation and altered cell behavior. The research here provides just one example of many.
Endothelial progenitor cells (EPCs), obtained from peripheral blood and identified as CD34 antigen-positive (CD34+) mononuclear cells, were marrow-derived stem cells and can differentiate into endothelial cells to promote neovascularisation in response to ischemic injury. Cell therapy using EPCs has been shown beneficial in ischaemia-related cardiovascular diseases (CVD) and emerged as useful substrates for neovascularization. However, some limitations make their clinical application difficult, such as heterogeneity in progenitor cell types, lack of standardization of specific surface markers and reduced number during ageing. Nonetheless, the angiogenic potential of EPCs has been an important target in regenerative medicine.
Numerous studies indicated that microRNA (miR or miRNA) is involved in post-transcriptional regulation of gene expression concerning diverse biological functions, including ageing and angiogenesis. A previous report showed that angiogenesis and tissue repair were regulated by miRNA-135a-3p via targeting p38 signalling in endothelial cells, revealing a link among miRNA, angiogenesis, and endothelial cells. In addition, increased miRNA-183-5p with age was involved in stem cell senescence. Furthermore, several studies have also addressed the regulation of miRNA during culture-induced senescence of vascular cells or in tissues.
These findings suggested that senescence and miRNAs may play an integrated role in modulating the pathologic processes of human CVD via the regulation of progenitor cell activity. We, therefore, in the present study explored the roles of hsa-microRNA (miR)-409-3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa-miR-409-3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with PP2A siRNA caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs.
Inhibited angiogenesis of young EPCs after miRNA-409-3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa-miR-409-3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa-miR-409-3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa-miR-409-3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis by regulating PP2A/p38 signalling.