A newly discovered mechanism controls whether muscle cells in blood vessels hasten the development of both atherosclerosis and Alzheimer's disease, according to an article published online in the journal Nature.
The study was led by the Gladstone Institute of Cardiovascular Disease (GICD) in San Francisco, with key contributions from the Aab Cardiovascular Research Institute at the University of Rochester School of Medicine and Dentistry.
Thanks to stem cells, humans develop from a single cell embryo into a complex being with about 250 unique cell types. As the fetus develops, cells divide and multiply (proliferate) in many generations and specialize (differentiate) with each generation until millions of functional cells result (bone, nerve, blood, skin, muscle, etc.). To serve specific roles in the body, some stem cells also switch back and forth between primitive, rapidly proliferating precursors and their mature, functioning, non-proliferating counterparts, a quality called "plasticity."
Among the most "plastic" of cells are vascular smooth muscle cells (VSMC), which form in layers around blood vessels, and by contracting or relaxing, regulate blood pressure. Because VSMC surround blood vessels that are continually becoming clogged by atherosclerosis, they must be ever ready to grow along with the vessel as it attempts, by growing, to remain open to blood flow despite fatty deposits and inflammation. If these efforts fail, heart attack or stoke may occur. Each time a vessel grows to avoid a clog, the VSMC surrounding it must grow too by reverting to their high-growth precursor form. Once a vessel reaches its growth limit, however, the growth that once kept vessels open begins adding to clogs by thickening vessel walls.
Past studies in Rochester have shown that 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), as part of a regulatory network that influences many genes. 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. For this reason the field has sought urgently to learn how myocardin levels are controlled, but without success.
Enter a research team led by Deepak Srivastava, M.D, director of GICD, world leaders in the characterization of microRNAs (miRNAs). These small, single-stranded molecules of ribonucleic acid (RNA), discovered in the Victor Ambros lab in 1993, fine-tune protein levels in all cells of the body. The GICD team discovered that miRNAs control VSMC differentiation and growth.
Gene expression is the process where information encoded in genes is converted into proteins, the workhorse molecules that make up the body's structures and carry its signals. While genes are encoded in chains of deoxyribonucleic acids (DNA), they are copied into chains of messenger ribonucleic acids (mRNA) that are "read" by cellular machines that build proteins. microRNAs bind to messenger RNAs, usually targeting them for breakdown or rendering them unfit to serve as templates for protein production.
The current study found that two miRNAs in particular, miR-143 and miR-145, are part of a molecular switch that determines whether VSMC 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. Surprisingly, miR-145 activated the expression of myocardin, which maintains VSMC in their mature form over their high-growth form.