Increased matrix metalloproteinase-1 activation enhances disruption and regression of k-RasV12-expressing arteriovenous malformation-like vessels

In this study, we sought to identify potential mechanisms by which k-RasV12 expressing EC tubes demonstrate an increased propensity to regress compared to controls. Activated K-Ras mutations play a role in a variety of pathological conditions, including arteriovenous malformations (AVMs), which are prone to bleed causing serious hemorrhagic complications. Previously, we reported that ECs expressing active k-RasV12 demonstrate markedly excessive lumen formation with widened and shortened tubes accompanied by reduced pericyte recruitment and basement membrane deposition, leading to deficient capillary network assembly. Here, we demonstrate that active K-Ras expressing ECs secrete greater amounts of MMP-1 proenzyme compared to control ECs, and readily convert this to increased levels of active MMP-1 through the action of plasmin or plasma Kallikrein (generated from their added zymogens). Active MMP-1 degrades 3D collagen matrices leading to more rapid and extensive regression of the active K-Ras expressing EC tubes, in conjunction with matrix contraction, compared to control ECs. Under conditions where pericytes protect control EC tubes from plasminogen- and MMP-1-dependent tube regression, this failed to occur with k-RasV12 ECs, due to reduced pericyte interactions. In summary, we show that k-RasV12 expressing EC vessels show an increased propensity to regress in response to serine proteinases through accentuated levels of active MMP-1, a novel pathogenic mechanism that may underlie hemorrhagic events associated with AVM lesions.