Abstract 183: Collagen Type V (Col V) Contributes to the Development of Aortic Dissections and Aneurysms

Abstract

Background: Negative remodeling of extracellular matrix (ECM) is a key pathological feature associated with aortic dissections and aneurysms. Col V is a minor fibrillar collagen that incorporates into growing fibrils with Col I, and is involved in regulating the geometry and tensile strength of ECM. Col V normally exists as α 1 (V) 2 α 2 (V) 1 heterotrimers but may present as α 1 (V) 3 homotrimers in pathological tissues. To experimentally increase the existence of α 1 (V) 3 homotrimer, we deleted the Col5a2 gene, which encodes the α2(V) chain. Col5a2 +/- mice showed increased compliance and reduced tensile strength in the skin and aorta. In the present study, we tested whether Col5a2 deficiency affects the pathogenesis of aortic dissections and aneurysms. Methods and Results: Six-month-old male Col5a2 +/- and Col5a2 +/+ mice on an Ldlr null background were infused with Angiontensin II (AngII). Mortality for Col5 a2 +/- mice within the first 7 days was 45% vs 0% for WT ( P <0.045, n=9), with 60% due to aortic arch rupture and 40% due to dissection. Among those that survived the 28 day treatment, 7/ 7 Col5a2 +/ - mice developed abdominal aortic aneurysm, defined as greater than or equal to 50% increase in the maximal external suprarenal diameter over infrarenal aorta, whereas 5/9 WT showed aneurysm dilatation. Compared to WT, aneurysm dilatations were significantly increased in Col5a2 +/ - mice (132.1 ± 8.5% vs 90.12 ± 9.6%, P <0.017). Histological analyses revealed marked disarray and loss of elastic fibers in Col5a2 +/- aortas and no difference in levels of fragmentation. Moreover, medial layer integrity was deteriorated in Col5a2 +/- mice and was associated with increased infiltration of macrophages. Conclusions: Collectively, our data suggest that haploinsufficiency for the α2(V) chain leads to media layer changes and increased susceptibility to aortic arch ruptures, dissections, and larger aortic aneurysms. The α2(V) chain may thus represent a novel candidate marker/target for the identification and treatment of aortic dissection and aneurysm.