Two miRNAs control how muscle cells in blood vessels switch between the precursor state and mature, functioning cells, according to scientists from the Gladstone Institute of Cardiovascular Disease and the Aab Cardiovascular Research Institute at the University of Rochester School of Medicine and Dentistry. These findings also elucidate the role of vascular smooth muscle cells (VSMCs) in atherosclerosis and Alzheimer’s.
The findings are published online in Nature in a paper is called “MiR-145 and miR-143 regulate smooth muscle cell fate and plasticity.”
Each time a vessel grows to avoid a clog, vascular smooth muscle cells surrounding it must grow as well by reverting to their high-growth precursor form. Past studies in Rochester showed that the transition of VSMC from fast-proliferating stem cells to mature cells and back is largely controlled by two proteins, myocardin and serum response factor (SRF). SRF anchors to certain snippets of DNA, while myocardin turns on the genes to which SRF sticks. Most of the genes turned on by myocardin/SRF in VSMC are needed for normal function.
When levels of myocardin decrease, as they do for some reason in vascular diseases like atherosclerosis, VSMC no longer work normally and vessel thickening ensues. Hence the scientists sought out to learn how myocardin levels are controlled.
Their research found that two miRNAs in particular, miR-143 and miR-145, are part of a molecular switch that determines whether VSMCs persist as high-growth precursors or mature into functioning muscle cells. miR-143 was found to block the expression of factors that promote proliferation by VSMC precursors. miR-145 activated the expression of myocardin, which maintains VSMCs in their mature form over their high-growth form.
Further testing in a mouse model found that expression of miR-143 and miR-145 was reduced to almost nothing where disease-related proliferation of VSMCs had thickened blood vessel walls. These findings suggest that miR-143 and miR-145 in partnership with myocardin maintain the normal balance between mature VSMCs and their precursors. Thus, researchers believe the drop in miR-143 and miR-145 levels seen in disease settings contributes greatly to vessel wall thickening, but that theory will need to be confirmed by further studies.
In addition, the investigators found that myocardin and serum response factor SRF activate genes that may influence the rate at which the brain can remove amyloid beta. In a February 2009 article in Nature Cell Biology, University of Rochester investigator Berislav Zlokovic, M.D., Ph.D., found that when SRF and myocardin are active, amyloid beta accumulates in VSMCs lining blood vessels. This paper was called “SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells.” The discovery that miR-145 encourages the expression of myocardin could explain why myocardin may occur in higher levels in Alzheimer’s disease.