Association of Hypoxia with Impaired Remodeling Mechanisms in the Abdominal Aortic Aneurysm (AAA) Wall

Abstract

AAA rupture occurs when wall stresses exceed the wall strength. We tested two hypotheses: 1) the AAA wall near thick intraluminal thrombus (ILT) exhibits impaired remodeling compared to wall near thin ILT and 2) macrophages (mΦ) cultured under hypoxic conditions exhibit altered enzyme expression compared to mΦ in normoxic conditions. For 1, pairs of AAA wall, selected based on disparate thicknesses of near ILT, were snap frozen. QPCR was used to compare the gene expression. Total wall thickness was measured on H&E sections. For 2, peripheral mononuclear cells were isolated from human buffy coats and cultured under hypoxic (2% O2) or normoxic (20% O2) conditions in serum‐free medium. Media levels of MMP‐9 were determined using ELISA. We found a down‐regulation of MMP‐2, MMP‐9, uPA, tPA, CD68, and collagen IV, and an up‐regulation of HO‐1, ORP‐150, ICAM‐1, IL‐12, IFN‐γ, and iNOS in AAA wall near thick ILT compared to AAA wall near thin ILT. AAA wall thickness was positively correlated (ρ=0.476) to ILT thickness. MΦ cultured in hypoxic conditions showed a marked decrease in secreted MMP‐9 activity and protein levels relative to mΦ cultured in normoxic conditions on collagen I or fibrin. The results support hypothesis 1, suggesting that compared to AAA wall near thin ILT, the AAA wall adjacent to a thick ILT has a more activated immune component and impaired remodeling mechanisms. Our results also suggest that the hypoxic environment of the AAA wall may lead to an alteration in protein expression by mΦ. This work was supported by NIH R01‐HL79313.