Two microRNAs keep smooth muscle cells on a leash. Now, Quintavalle et al. have uncovered a molecular pathway that sets the cells free and might worsen the arterial buildup of atherosclerosis.
When sedentary smooth muscle cells start crawling, they can cause trouble. The cells pile into the vessel lesions that form during atherosclerosis, and they can spur restenosis, the re-narrowing of an artery after an angioplasty or insertion of a stent. Previous studies have shown that two microRNAs, miR-143 and miR-145, prevent cells from switching to the mobile form. But researchers didn't know what controlled the microRNAs.
Quintavalle et al. created mice that lack miR-143 and miR-145. In a culture dish, a smooth muscle cell begins its journey by extending a membrane “foot” called a podosome. Using immunoelectron microscopy, the team identified smooth muscle podosomes in aortic tissue from the mice, the first time the structures have been spotted in vivo. The researchers showed that the microRNAs normally halt podosome extension, in part by down-regulating protein kinase C ε, PDGF receptor α, and fuscin.
Quintavalle et al. teased out the molecular pathway that unleashes smooth muscle cells. The circuit begins with platelet-derived growth factor (PDGF), which is overactive in patients with atherosclerosis and restenosis. PDGF activates Src, which reduces levels of the microRNAs by inhibiting p53. One of p53's tasks is spurring production of miR-143 and miR-145.
The results suggest the microRNAs as a potential treatment for atherosclerosis—though researchers first have to develop a practical way to deliver the molecules to vascular cells. The work also raises the question of whether these microRNAs shackle cancer cells, which crawl with podosome-like structures called invadopodia.