Extracellular matrix, regional heterogeneity of the aorta, and aortic aneurysm

Abstract

Aortic aneurysm is an asymptomatic disease with dire outcomes if undiagnosed. Aortic aneurysm rupture is a significant cause of death worldwide. To date, surgical repair or endovascular repair (EVAR) is the only effective treatment for aortic aneurysm, as no pharmacological treatment has been found effective. Aortic aneurysm, a focal dilation of the aorta, can be formed in the thoracic (TAA) or the abdominal (AAA) region; however, our understanding as to what determines the site of aneurysm formation remains quite limited. The extracellular matrix (ECM) is the noncellular component of the aortic wall, that in addition to providing structural support, regulates bioavailability of an array of growth factors and cytokines, thereby influencing cell function and behavior that ultimately determine physiological or pathological remodeling of the aortic wall. Here, we provide an overview of the ECM proteins that have been reported to be involved in aortic aneurysm formation in humans or animal models, and the experimental models for TAA and AAA and the link to ECM manipulations. We also provide a comparative analysis, where data available, between TAA and AAA, and how aberrant ECM proteolysis versus disrupted synthesis may determine the site of aneurysm formation.

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

“…In stark contrast to the effect in ECs, SMCs in alk5 mutants exhibit reduced proliferation and therefore reduced coverage of the OFT, explaining the lost integrity of the wall. This reduced SMC coverage is in agreement with the vascular defects reported in mice lacking Alk5 signaling globally, as well as in patients affected by aortic aneurysms (Larsson et al, 2001; Jana et al, 2019).…”

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

“…Interestingly, many of the phenotypes we observed are similar to defects associated with aortopathies in clinical settings, pathologies often derived from mutations in TGF-β pathway genes (Loeys et al, 2006;Matyas et al, 2006;Camerota et al, 2019). At the morphological level, we observed that alk5a mutants present a thinning of the OFT outer wall, similar to patients affected by aortic aneurysms prone to dissection (Van Puyvelde et al, 2016;Jana et al, 2019). It is also interesting to note that the volume of the OFT wall decreased according to the age and size of the fish, similar to the decrease in aortic wall thickness in older patients (Fhayli et al, 2019;Clift et al, 2020).…”

ADAM (a Disintegrin and Metalloproteinase) 15 Deficiency Exacerbates Ang II (Angiotensin II)–Induced Aortic Remodeling Leading to Abdominal Aortic Aneurysm

“…Aortic aneurysm results from a series of adverse structural and cellular events, such as degradation of the ECM (extracellular matrix), loss or dysfunction of the endothelial cells (ECs) 1 and smooth muscle cells (SMCs). 2 , 3 Abdominal aortic aneurysm (AAA) is more prevalent in old men (≈1%–2% of 65 year olds) than in women (≈0.5% of 70 year olds). 4 – 6 Although linked to atherosclerosis, AAA can also occur in the absence of and independent from atherosclerosis and metabolic complications.…”