Sunday, 3 September 2006

Abstract

Purpose: Phosphoinositide 3-kinases (PI3K) belong to a conserved family of enzymes regulating important cellular processes such as cell survival and proliferation. Although PI3K signalling has been linked to vascular endothelial growth factor (VEGF) receptor activation, the specific roles of PI3Ks in the angiogenic process are unknown. In this study we tested the hypothesis that PI3Kγ activation is important in the collateral vessel development following hindlimb ischemia. Methods: To test this hypothesis, we ligated the femoral artery in wild type mice (129/B6, WT) and in PI3Kγ knockout mice (129/B6, PI3Kγ-/-). Results: Following surgery, PI3Kγ-/-mice displayed increased rates of amputation and deambulatory impairment. 28 days after surgery, laser doppler perfusion imaging showed significantly reduced blood flow recovery in PI3Kγ-/-mice compared to WT (ischemic over not-ischemic limb blood flow: WT =0.95 ± 0.04; PI3Kγ-/-= 0.73 ± 0.03, p<0.01), increased interstitial fibrosis (% area of fibrosis: WT = 1.7 ± 0.5; PI3Kγ-/-= 3.2 ± 0.8, p<0.01) and marked calf muscle atrophy following hindlimb ischemia (30% reduction in calf weight in PI3Kγ-/-vs. WT, p<0.01). In contrast to WT mice, hindlimb ischemia did not induce in PI3Kγ-/-mice a significant increase in the levels of VEGF, CD4, CD8, interleukin 16 (IL16) and phospho-ERK, suggesting that PI3Kγ might play a crucial role in the regulation of multiple signalling pathways involved in collateral vessel development following hindlimb ischemia. Conclusions: These results show a pivotal role of PI3Kγ in regulating collateral vessel development following hindlimb ischemia highlighting novel possible therapeutic strategies to enhance collateral vessel development in response to peripheral ischemia. 158 EDA promotes collateral artery growth through TLR2/TLR4 signaling