Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization

Fabiana Baganha,Wietske Voorham,Paul H. A. Quax,Rob C. M. de Jong,Erna A. Peters,J. Wouter Jukema,Mirela Delibegovic,Margreet R. de Vries

doi:10.1007/s10456-021-09767-9

Fabiana Baganha, Wietske Voorham + Show 6 more

Open Access

https://doi.org/10.1007/s10456-021-09767-9

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Abstract

ObjectiveStatins pleiotropically provide additional benefits in reducing atherosclerosis, but their effects on intraplaque angiogenesis (IPA) and hemorrhage (IPH) remain unclear. Therefore, we discriminated statin’s lipid-lowering dependent and independent effects on IPA and IPH.Approach and resultsApoE3*Leiden mice are statin-responsive due to ApoE and LDLR presence, but also allow to titrate plasma cholesterol levels by diet. Therefore, ApoE3*Leiden mice were fed a high-cholesterol-inducing-diet (HCD) with or without atorvastatin (A) or a moderate-cholesterol-inducing-diet (MCD). Mice underwent vein graft surgery to induce lesions with IPA and IPH. Cholesterol levels were significantly reduced in MCD (56%) and HCD + A (39%) compared to HCD with no significant differences between MCD and HCD + A. Both MCD and HCD + A have a similar reduction in vessel remodeling and inflammation comparing to HCD. IPA was significantly decreased by 30% in HCD + A compared to HCD or MCD. Atorvastatin treatment reduced the presence of immature vessels by 34% vs. HCD and by 25% vs. MCD, resulting in a significant reduction of IPH. Atorvastatin’s anti-angiogenic capacity was further illustrated by a dose-dependent reduction of ECs proliferation and migration. Cultured mouse aortic-segments lost sprouting capacity upon atorvastatin treatment and became 30% richer in VE-Cadherin expression and pericyte coverage. Moreover, Atorvastatin inhibited ANGPT2 release and decreased VE-Cadherin(Y685)-phosphorylation in ECs.ConclusionsAtorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization.

Highlights

Statins are currently the principal drug in primary and secondary prevention of coronary artery disease [1]
Our findings suggest that atorvastatin reduces intraplaque angiogenesis and intraplaque hemorrhage independent of its lipid lowering effects in vivo
To confirm the pleiotropic effect of atorvastatin on intraplaque angiogenesis, we studied the effects of increasing doses of atorvastatin (0.05 μg/ml, 0.5 μg/ml and 5 μg/ml) on the capacity of Human umbilical vein endothelial cells (HUVEC) to proliferate and migrate

Summary

Introduction

Statins are currently the principal drug in primary and secondary prevention of coronary artery disease [1]. Many studies demonstrated that statins can pleiotropically improve endothelial cell (EC) function [4,5,6,7] and inflammation [8, 9], providing an additional benefit in the reduction of atherosclerosis [10,11,12,13]. ECs proliferate and migrate to form neovessellike structures and overcome the oxygen demand in the plaque. These neovessels frequently have an immature nature, characterized by a discontinuous basement membrane, a lack of EC junctions and poor pericyte coverage [17]. Extravasated red blood cells are the main components of IPH and play a major role in cholesterol accumulation and monocyte recruitment into the plaque, initiating a vicious cycle that leads to further plaque destabilization [19]

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