No abstract

C ollateral arterial growth (arteriogenesis) plays a crucial role in ischemic stroke and is a key factor that defines the severity and functional prognosis of this disease. 1 The circle of Willis and leptomeningeal anastomoses are typical intracranial collaterals. 2 In the case of middle cerebral artery occlusion, the Circle of Willis is no longer able to contribute collateral blood supply and leptomeningeal anastomoses become the primary source of collateral blood flow. We previously reported that unilateral common carotid artery (CCA) occlusion induces ipsilateral leptomeningeal collateral growth after 14 days in rodents. 3,4 Using this established model to estimate leptomeningeal arteriogenesis, we showed that hematopoietic factors enhance arteriogenesis in mice. 3,5 We also demonstrated that leptomeningeal collateral growth induced by cerebral hypoperfusion is impaired in spontaneous hypertensive rats 4 and apolipoprotein E-knockout mice. 6 Vascular risk factors induce vascular dysfunction and may be related to impaired arteriogenesis. Diabetes mellitus is also a major vascular risk factor because the prevalence of hypertension, dyslipidemia, and diabetes mellitus is increasing worldwide. Diabetes mellitus is associated with an increased risk of first ischemic stroke, and 60% to 70% patients with ischemic stroke have diabetes mellitus or prediabetes mellitus. 7 It was previously reported that diabetes mellitus impairs arteriogenesis in peripheral 8 and coronary arteries, 9,10 but it is not fully understood whether it impairs arteriogenesis in the cerebral vessels.Background and Purpose-Leptomeningeal collateral growth is a key factor that defines the severity of ischemic stroke.Patients with stroke generally have vascular risk factors, such as diabetes mellitus; however, consensus is lacking on how diabetes mellitus affects leptomeningeal arteriogenesis. We investigate the influence of diabetes mellitus on the leptomeningeal arteriogenesis. Methods-We measured the vessel diameter of the leptomeningeal anastomoses 14 days after the common carotid artery occlusion in db/db, db/+, and streptozotocin-induced hyperglycemic mice. In another set of these mice, we measured the infarct volume attributed to subsequent middle cerebral artery occlusion 14 days after the common carotid artery occlusion. Mac-2-positive cells on the dorsal brain surface and the mRNA expression of several macrophage-related factors in the cerebral cortex were examined. Finally, we tested whether the leptomeningeal arteriogenesis could be restored by pharmaceutical intervention in the db/db mice. Results-Cerebral hypoperfusion led to significant ipsilateral leptomeningeal collateral growth in db/+ mice and streptozotocin-induced hyperglycemic mice. The collateral growth contributed to reduced infarct volume. In contrast, leptomeningeal arteriogenesis was impaired in the db/db mice. The number of Mac-2-positive cells was increased and tumor necrosis factor-α mRNA expression was induced after common carotid artery occlusion in the db/+ mi...

Thrombin aggravates ischemic stroke and activated protein C (APC) has a neuroprotective effect. Both proteases interact with protease-activated receptor 1, which exhibits functional selectivity and leads to G-protein- and β-arrestin-mediated-biased signal transduction. We focused on the effect of β-arrestin in PAR-1-biased signaling on endothelial function after stroke or high-fat diet (HFD). Thrombin had a rapid disruptive effect on endothelial function, but APC had a slow protective effect. Paralleled by prolonged MAPK 42/44 signaling activation by APC via β-arrestin-2, a lower cleavage rate of PAR-1 for APC than thrombin was quantitatively visualized by bioluminescence video imaging. HFD-fed mice showed lower β-arrestin-2 levels and more severe ischemic injury. The expression of β-arrestin-2 in capillaries and PDGF-β secretion in HFD-fed mice were reduced in penumbra lesions. These results suggested that β-arrestin-2-MAPK-PDGF-β signaling enhanced protection of endothelial function and barrier integrity after stroke.