Abdominal aortic aneurysms (AAA) are defined as a progressive weakening of the aortic wall, leading to gradual dilatation. We hypothesize that dysfunction of vascular smooth muscle cells (vSMC), the major cell type within the aortic wall, plays a paramount role in AAA pathophysiology. The aim of this study is to investigate in vitro contractility of human AAA vSMC compared to non-pathologic vSMC, and to find the underlying mechanism of altered in vitro contractility of vSMC derived from AAA patients.
Contractility of vSMC isolated from biopsies from AAA patients (n=39) and controls (n=18, vSMC derived from non-dilated aortas of post-mortem heart beating kidney transplant donors) was measured using Electric Cell-substrate Impedance Sensor. vSMC were stimulated with ionomycin (Ca2+ ionophore which induces a contractile response in adherent vSMC by the influx of extracellular Ca2+). To investigate the underlying mechanism of impaired vSMC contractility and the involved proteins a (phospho)proteomics analysis was performed in vSMC lysates of AAA patients (n=24) and controls (n=8).
vSMC contractility of AAA patients showed more variability compared to control vSMC. To define normal vSMC contractility range, mean contractility including ± 2 standard deviations (2SD) of the control cell lines was determined (83,51% ± 6,48%). AAA patients' vSMC were divided into subgroups based on this control vSMC contractility range (AAA-Low contracting: mean: 70,63%, SD: 5,51% (n=8); AAA-Normal contracting: mean: 83.69%, SD: 3.35% (n=22); AAA-High contracting: mean: 91.72%, SD: 1.22% (n=9)). The differences in vSMC contraction in AAA patients is correlated to changes in extracellular matrix and cell adhesion proteins and by pathways related to energy production.
vSMC contractility is altered in certain subgroups of AAA patients and might therefore play a role in AAA pathophysiology. Finding proteins involved in altered vSMC contractility is of clinical importance since it can represent potential targets for novel non-invasive treatments for prevention and/or stabilization of AAA.
This project is funded by the Dutch Heart foundation, Dekkerbeurs 2019T065 Senior clinical scientist grant.