Maintaining healthy perivascular stromal cells: Zooming in on vascular smooth muscle cell and pericyte biology

My first scientific love, the vascular smooth muscle cell (VSMCs) is the most abundant cell type in the artery wall. In healthy arteries, VSMCs serve to maintain vascular tone, with intrinsic and extrinsic factors influencing their control of blood flow and blood pressure in the coronary and peripheral arteries. Upon vascular injury, VSMCs undergo a well-established phenotypic shift from a contractile to a fibroproliferative, migratory state, a physiologic response that aids in repair of the damaged vessel. This fibroproliferative activity of the VSMC can aid in resolution of initial damage , but is also tightly linked with pathophysiological situations such as coronary artery disease (CAD), in-stent restenosis and peripheral arterial disease (PAD). Therefore, to limit these clinical manifestations, VSMCs must revert to the contractile phenotype, a shift that reliant on the restoration of the expression of a broad repertoire of alternatively spliced contractile apparatus proteins. We have identified a critical role for the RNA-binding properties of Quaking in regulating this shift in phenotype, by guiding splicing of the transcriptional co-activator myocardin pre-mRNA (link to de Bruin et al., Circulation Research, 2013).

Transitioning from macrovascular diseases (such as atherosclerosis and (re)stenosis), my research group is also interested in gaining a better understanding of the post-transcriptional role for Quaking in microvascular disease(s). Destabilization of microvessels is initiated by chronic activation of endothelial cells (ECs) by cardiovascular risk factors that inflict the loss of pericytes with a subsequent loss of EC cell-cell junctions. This leads to vessel leakage and induction of an pro-angiogenic response. This process is mediated by several angioregulatory factors, including pericyte-derived anti-inflammatory factor Angiopoietin-1 (Ang-1) and the pro-inflammatory EC factor Angiopoietin-2 (Ang-2). In normal physiology, Ang-1 binding to the endothelial Tie-2 receptor stabilizes the microvasculature. However, in clinical conditions such as diabetes or transplant rejection, Ang-2 can compete for this binding and instigate pro-inflammatory responses that promote destabilization, vessel leakage and inflammation. Given our identification that Quaking controls endothelial barrier function (link to de Bruin et al., Scientific Reports, 2016) and VSMC function (see above), the RNA-binding properties are likely critical for the maintenance of a healthy microcirculation.