Pharmacological strategies to inhibit intra-plaque angiogenesis in atherosclerosis

Abstract

Atherosclerosis is a complex multifactorial disease that affects large and medium-sized arteries. Rupture of atherosclerotic plaques and subsequent acute cardiovascular complications remain a leading cause of death and morbidity in the Western world. There is a considerable difference in safety profile between a stable and a vulnerable, rupture-prone lesion. The need for plaque-stabilizing therapies is high, and for a long time the lack of a suitable animal model mimicking advanced human atherosclerotic plaques made it very difficult to make progress in this area. Evidence from human plaques indicates that intra-plaque (IP) angiogenesis promotes atherosclerosis and plaque destabilization. Although neovascularization has been widely investigated in cancer, studies on the pharmacological inhibition of this phenomenon in atherosclerosis are scarce, mainly due to the lack of an appropriate animal model. By using ApoE Fbn1 mice, a novel model of vulnerable plaques, we were able to investigate the effect of pharmacological inhibition of various mechanisms of IP angiogenesis on plaque destabilization and atherogenesis. In the present review, we discuss the following potential pharmacological strategies to inhibit IP angiogenesis: (1) inhibition of vascular endothelial growth factor signalling, (2) inhibition of glycolytic flux, and (3) inhibition of fatty acid oxidation. On the long run, IP neovascularization might be applicable as a therapeutic target to induce plaque stabilization on top of lipid-lowering treatment.

Three-Dimensional Imaging of Intraplaque Neovascularization in a Mouse Model of Advanced Atherosclerosis

“…These features are rarely seen in murine atherosclerosis models but are frequently observed in advanced human plaques. IP neovessels in ApoE −/− Fbn1 C1039G+/− mice on the WD likely arise from the adventitial vasa vasorum and sprout out of the media into the plaque [9]. Although the exact role of IP neovessels is not exactly understood, it is important to note that such structures are immature and leaky.…”

Vulnerable Plaque, Characteristics, Detection, and Potential Therapies

“…Yet, a great challenge has been the finding of an atherosclerosis model of spontaneous plaque rupture with humanized endpoints such as MI, stroke, and unexpected death. Recently, these features were proposed in apo E −/− Fbn1C1039G +/− mice [143]. This model could evaluate potential plaque-stabilizing therapies to better define systemic anti-atherosclerotic factors and their mechanisms.…”

“…Anti-angiogenic medications used in clinical trials (mostly anti-VEGF/VEGFR) for anticancer treatments have been associated with a risk for CV adverse effects, and further studies are needed [142,180]. More recently, various compounds have been studied to inhibit IP angiogenesis with mechanisms of action that interfere with angiogenesis [141,142,143] (Table 2). Studies based on a blocking antibody (bevacizumab against VEGF-A, axitinib against VEGF receptor tyrosine kinase, and DC101 against VEGFR-2) have shown potential ability for the treatment of IP angiogenesis and hemorrhage [143].…”

“…More recently, various compounds have been studied to inhibit IP angiogenesis with mechanisms of action that interfere with angiogenesis [141,142,143] (Table 2). Studies based on a blocking antibody (bevacizumab against VEGF-A, axitinib against VEGF receptor tyrosine kinase, and DC101 against VEGFR-2) have shown potential ability for the treatment of IP angiogenesis and hemorrhage [143]. Few studies targeting neovascularization have been documented [143], possibly because of the absence of relevant animal models.…”

bFGF blockade reduces intraplaque angiogenesis and macrophage infiltration in atherosclerotic vein graft lesions in ApoE3*Leiden mice

“…Atherosclerosis is a chronic disease that culminates with plaque rupture often leading to acute cardiovascular events. Crucial factors for plaque instability and therefore for plaque rupture are not the size, but rather the composition of the atherosclerotic plaques 1 . Distinctive features like large necrotic cores, intraplaque angiogenesis, intraplaque haemorrhage, high macrophage content and a thin fibrous cap are known for their role in plaque destabilization 2 .…”