Acetylsalicylic Acid, but Not Clopidogrel, Inhibits Therapeutically Induced Cerebral Arteriogenesis in the Hypoperfused Rat Brain

Abstract

This study investigated the effects of acetylsalicylic acid (ASA) and clopidogrel, standardly used in the secondary prevention of vascular occlusions, on cerebral arteriogenesis in vivo and in vitro. Cerebral hypoperfusion was induced by three-vessel occlusion (3-VO) in rats, which subsequently received vehicle, ASA (6.34 mg/kg), or clopidogrel (10 mg/kg). Granulocyte colony-stimulating factor (G-CSF), which enhanced monocyte migration in an additional cell culture model, augmented cerebrovascular arteriogenesis in subgroups (40 lg/kg). Cerebrovascular reactivity and vessel diameters were assessed at 7 and 21 days. Cerebrovascular reserve capacity was completely abolished after 3-VO and remained severely compromised after 7 (À14 ± 14%) and 21 (À5 ± 11%) days in the ASA groups in comparison with controls (4 ± 5% and 10 ± 10%) and clopidogrel (4 ± 13% and 10 ± 8%). It was still significantly decreased when ASA was combined with G-CSF (1 ± 4%) compared with G-CSF alone (20 ± 8%). Posterior cerebral artery diameters confirmed these data. Monocyte migration into the vessel wall, improved by G-CSF, was significantly reduced by ASA. Acetylsalicylic acid, but not clopidogrel, inhibits therapeutically augmented cerebral arteriogenesis.

The Ins and Outs of the BCCAo Model for Chronic Hypoperfusion: A Multimodal and Longitudinal MRI Approach

“…These findings are in agreement with the notion acquired in other vascular beds that, contrarily to angiogenesis, arteriogenesis is not induced by ischemia but results from the increased fluid shear stress derived from vessel occlusion [23]. Among the molecular determinants of arteriogenesis, expression of growth factors, adhesion molecules and chemokines, such as monocyte chemoattractant protein-1, in vascular smooth muscle cells have been identified as a critical factor for the initiation of arteriogenesis [56,57,58], together with monocyte recruitment to the arteries [59]. These effects promote vascular remodeling and are thought to be beneficial by restoring blood flow after arterial occlusion [60].…”

PPARγ activation inhibits cerebral arteriogenesis in the hypoperfused rat brain

“…Hemodynamic CVRC was calculated from CBF (Duelsner et al . ,b). After femoral arterial and venous catheterization and blood gas analysis, LDF was measured continuously over the left temporal hemicranium; 30 μg kg −1 acetazolamide were injected into the left femoral vein, LDF was recorded, and CVRC was calculated as described, followed by another blood gas analysis, at the following time points: (i) untreated non‐operated rats ( n = 8): day 0, (ii) 3‐VO only ( n = 8): post‐operative day 1, (ii) 3‐VO plus pioglitazone: day 21, (iv) 3‐VO and G‐CSF plus pioglitazone: day 7.…”

“…Three‐vessel occlusion induces collateral artery growth in the posterior cerebral artery (PCA), identified as the region of interest (ROI) for this study (Duelsner et al . ,b).…”

“…To evaluate effects of PPARγ activation on therapeutically induced cerebral arteriogenesis, rats received G‐CSF (40 μg kg −1 every other day; Duelsner et al . ,b; Fig. a) or G‐CSF plus pioglitazone (2.8 mg kg −1 q.d.)…”

Endothelial Progenitor Cells Augment Collateralization and Hemodynamic Rescue in a Model of Chronic Cerebral Ischemia

“…20 Functional Recovery of Hemodynamic Impairment after Treatment with Embryonic-Endothelial Progenitor Cells The perfusion response (CVRC) after application of a vasodilatory stimulus has previously been used as a functional readout by others and our group with comparable results. 4,26 Occlusion of three of the four major brain-feeding arteries leads to a completely suppressed CVRC, which continued for the observation period of 3 weeks. Intravenous application of e-EPC, however, improved CVRC within 1 week of treatment.…”