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

OBJECTIVE: Statins 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 RESULTS: ApoE3*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. CONCLUSIONS: Atorvastatin 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.

Circulating Microparticles in Patients with Symptomatic Carotid Disease Are Related to Embolic Plaque Activity and Recent Cerebral Ischaemia.

BACKGROUND AND PURPOSE: In order to assess the association of microparticles derived from activated platelets (PMP) or endothelial cells (EMP) with risk markers for recurrent embolic events in patients with symptomatic carotid artery disease, we studied the associations between PMP/EMP and three risk markers: plaque haemorrhage (PH), micro-embolic signals and cerebral diffusion abnormalities. METHODS: Patients with recently symptomatic high-grade carotid artery stenosis (60-99%, 42 patients, 31 men; mean age 75 ± 8 years) and 30 healthy volunteers (HV, 11 men; mean age 56 ± 12 years) were prospectively recruited. Patients were characterised by carotid magnetic resonance imaging (presence of PH [MRI PH]), brain diffusion MRI (cerebral ischaemia [DWI+]) and transcranial Doppler ultrasound (micro-embolic signals [MES+]). PMP and EMP were classified by flow cytometry and expressed as log-transformed counts per microlitre. RESULTS: MES+ patients (n = 18) had elevated PMP (MES+ 9.61 ± 0.57) compared to HV (8.80 ± 0.73; p < 0.0001) and to MES- patients (8.55 ± 0.85; p < 0.0001). Stroke patients had elevated PMP (9.49 ± 0.64) and EMP (6.13 ± 1.0) compared to non-stroke patients (PMP 8.81 ± 0.73, p = 0.026, EMP 5.52 ± 0.65, p = 0.011) and HV (PMP 8.80 ± 0.73, p = 0.007, and EMP 5.44 ± 0.47, p = 0.006). DWI+ patients (n = 16) showed elevated PMP (DWI+ 9.53 ± 0.64; vs. HV, p = 0.002) and EMP (DWI+ 5.91 ± 0.99 vs. HV 5.44 ± 0.47; p = 0.037). Only PMP but not EMP were higher in DWI+ versus DWI- patients (8.67 ± 0.90; p = 0.002). No association was found between PMP and EMP with MRI PH. CONCLUSIONS: PMP and EMP were associated with stroke and recent cerebrovascular events (DWI+) but only PMP were also associated with ongoing (MES+) thrombo-embolic activity suggesting a differential biomarker potential for EMP to index cerebral ischaemia while PMP may predict on-going thrombo-embolic activity.