Progressive Development of Aberrant Smooth Muscle Cell Phenotype in Abdominal Aortic Aneurysm Disease

Abstract

Abdominal aortic aneurysm (AAA) is a silent, progressive disease with a high mortality and an increasing prevalence with aging. Smooth muscle cell (SMC) dysfunction contributes to gradual dilatation and eventual rupture of the aorta. Here we studied phenotypic characteristics in SMC cultured from end-stage human AAA (≥5 cm) and cells cultured from a porcine carotid artery (PCA) model of early and end-stage aneurysm. Human AAA-SMC presented a secretory phenotype and expressed elevated levels of the differentiation marker miR-145 (2.2-fold, p < 0.001) and the senescence marker SIRT-1 (1.3-fold, p < 0.05), features not recapitulated in aneurysmal PCA-SMC. Human and end-stage porcine aneurysmal cells were frequently multi-nucleated (3.9-fold, p < 0.001, and 1.8-fold, p < 0.01, respectively, vs. control cells) and displayed an aberrant nuclear morphology. Human AAA-SMC exhibited higher levels of the DNA damage marker γH2AX (3.9-fold, p < 0.01, vs. control SMC). These features did not correlate with patients' chronological age and are therefore potential markers for pathological premature vascular aging. Early-stage PCA-SMC (control and aneurysmal) were indistinguishable from one another across all parameters. The principal limitation of human studies is tissue availability only at the end stage of the disease. Refinement of a porcine bioreactor model would facilitate the study of temporal modulation of SMC behaviour during aneurysm development and potentially identify therapeutic targets to limit AAA progression.

Divergent effects of canonical and non‐canonical TGF‐β signalling on mixed contractile‐synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms

“…Phenotypic ‘switching’ of aortic constituent cells contributes to aneurysm formation in abdominal, descending thoracic and aortic root aneurysms . This study confirms the simultaneous enhancement of both contractile and synthetic gene sets in MFS proposed by Crosas‐Molist et al who similarly observed an overexpression of both contractile markers and collagen I in human MFS specimens.…”

Role of microRNA-145 in DNA damage signalling and senescence in vascular smooth muscle cells of Type 2 diabetic patients

“…However, T2DM-SMC cells were unequivocally distinct from ND cells, lending weight to the idea that additional mechanisms conferring accelerated aging and senescence in T2DM may be responsible. In support of this hypothesis, we recently demonstrated in cultured human SMC of both aortic and venous origin, that miRNA-145 expression levels did not correlate with chronological age but were elevated in abdominal aortic aneurysm SMC; a disorder associated with accelerated vascular aging (19).…”

“…SMC cultured on glass coverslips were fixed in 4% PFA prior to immunostaining with phosphohistone H2AX (H2AX) antibody (Cell Signaling Technologies #2577) as described previously (19). Coverslips were mounted using Prolong Gold antifade reagent containing DAPI (Thermo-Fisher Scientific) and imaged on a Zeiss 700 confocal microscope.…”

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

“…Phenotype transformation of vascular smooth muscle cells (VSMC) is considered a driving force of many vascular diseases, including aortic aneurysms (Bennett et al, 2016;Hortells et al, 2018;Riches et al, 2018). Human abdominal aortic aneurysm (AAA) is an age-related disease, de ned by dilation of the aorta by more than half of the original diameter.…”

“…Today, VSMC phenotypic switching and calci cation are considered key in AAA formation (Petsophonsakul et al, 2019;Riches et al, 2018) and the phenotypic modulation has been shown to be an early event in the aorta before aneurysm growth (Ailawadi et al, 2009).…”