Oxidized Phospholipids Stimulate Angiogenesis Via Autocrine Mechanisms, Implicating a Novel Role for Lipid Oxidation in the Evolution of Atherosclerotic Lesions

Abstract

Abstract-Angiogenesis is a common feature observed in advanced atherosclerotic lesions. We hypothesized that oxidized phospholipids (OxPLs), which accumulate in atherosclerotic vessels can stimulate angiogenesis. We found that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) stimulated the formation of sprouts from endothelial cell spheroids and promoted growth of capillaries into Matrigel plugs in mice. OxPLs stimulated expression of vascular endothelial growth factor (VEGF) in vivo and in several normal and tumor cell types in vitro. Key Words: oxidized phospholipids Ⅲ atherosclerosis Ⅲ angiogenesis Ⅲ plaque destabilization T he adventitial layer of human coronary arteries contains a network of microvasculature, termed vasa vasorum, that delivers oxygen and nutrients to the outer layers of the arterial wall. In contrast to the adventitia, the intima and the inner media of normal large arteries usually do not contain capillaries. However, during atherosclerotic plaque formation, microvessels appear in the thickened intima and media of more that 40% of lesions. 1,2 These neovessels originate mainly from the adventitial vasa vasorum and support growth of atherosclerotic intima beyond the critical thickness limited by diffusion from the major arterial lumen. 3 It has been widely hypothesized that neovascularization is a causative factor for atherosclerotic plaque growth and destabilization. Although these issues are difficult to address in a direct experiment (discussed in Khurana et al 4 ), there is much indirect evidence suggesting that neovascularization can influence the evolution of atheroma via several mechanisms. The density of vasa vasorum strongly correlates with the number of infiltrating mononuclear cells, suggesting that neovessels are an important route for the entry of leukocytes into advanced lesions. 2,5 Furthermore, intraplaque microvascular hemorrhages provide blood cell-derived lipids that deposit in the lipid core. 6,7 Microvessels are functionally important in atherogenesis as illustrated by the ability of angiogenesis inhibitors angiostatin and TNP-470 to reduce angiogenesis and inhibit the development of lesions in apoE knockout mice. 5,8 In contrast, angiogenic stimuli such as vascular endothelial growth factor (VEGF) promote lesion development. 9 Such data strongly suggest that formation of vasa vasorum stimulates the progression of atherosclerotic lesions.In addition to a role in plaque growth, the formation of neovessels potentially can decrease the stability of atheroma because of digestion of plaque tissue by metalloproteases secreted by growing capillaries. Indeed, unstable and ruptured atherosclerotic plaques are characterized by an increased density of plaque microvessels. 10,11 Hypoxia is among the strongest known angiogenic stimuli also thought to play a role in the development of intimal neovascularization. 12 However, additional microenvironmental factors independent of lesion thickness may also be important for plaque angiogenesis. In apoE-deficient mice,

Small Concentrations of oxLDL Induce Capillary Tube Formation From Endothelial Cells via LOX-1–Dependent Redox-Sensitive Pathway

“…Whereas angiogenesis may facilitate healing of ischemic tissues, 39 progressive angiogenesis in a primary atherosclerotic lesion may cause plaque expansion and plaque vulnerability, and enhance the risk of significant disease by promoting intravascular thrombosis. 40,41 In the present study, we for the first demonstrate that small concentrations of oxLDL induce capillary tube formation from endothelial cells. The formation of capillaries in response to oxidized lipids, their precise source and clinical relevance need to be further examined in animal models and humans.…”

Inhibition of IRE1 modifies hypoxic regulation of G6PD, GPI, TKT, TALDO1, PGLS and RPIA genes expression in U87 glioma cells

“…It is reasonable to suggest, that combined impact of hy poxia and IRE1 inhibition on the expression of key regulatory factors may contribute to the decreased proliferation potential of IRE1 knockdown glioma cells. Similar results were obtained previously for hypoxic regulation of TP53, zMAt3, IGFBP6, IG-FBP7, NOV, WISP2, AtF3, tBX3, FOXF1, HOXC6 and some other genes [8,10,37,4145].…”

“…Statistical analysis was performed according to Student's ttest using Excel program as described previously [37]. All values are expressed as mean ± SEM from triplicate measure ments performed in 4 independent experiments.…”

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

“…All values are expressed as mean ± SEM from triplicate measurements performed in four independent experiments. Statistical analysis was performed as described previously (Bochkov et al 2006). Th e amplifi ed DNA fragments were also analyzed on a 2% agarose gel and that visualized by SYBR* Safe DNA Gel Stain (Life Technologies, Carlsbad, CA, U.S.A.).…”