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. 2021 Oct 26;78(23):7355–7378. doi: 10.1007/s00018-021-03979-4

Fig. 4.

Fig. 4

Molecular mechanisms regulated by miR-34a in vascular smooth muscle cells leading to Vascular Calcification and Abdominal Aortic Aneurism. Different stimuli, such as aging, Angiotensin II (Ang II), and hyperphosphatemia (high levels of calcium and phosphate, Ca2+; P), are able to induce miR-34a levels in vascular smooth muscle cells (VSMCs). miR-34a increase inhibits VSMCs proliferation via upregulation of p21 and direct downregulation of the receptor tyrosine kinase AXL and promotes VSMCs senescence by targeting the sirtuin 1 (SIRT1). miR-34a also influences VSMCs SASP acquisition by promoting the secretion of specific SASP factors, including IL6, and in this way favors vascular and systemic inflammation and senescence spreading. Senescent VSMCs are more prone to switch to an osteoblastic-like phenotype responsible for vascular calcification onset. Angiotensin II (Ang II) induces miR-34a levels through the induction of Methyltransferase-like 3 (METTL3) expression that enhances miR-34a maturation in VSMCs and eventually favors abdominal aortic aneurism (AAA) development. In red are highlighted known direct targets of miR-34a