Chronic Elevation of Tumor Necrosis Factor-α Mediates the Impairment of Leptomeningeal Arteriogenesis in db/db Mice

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...

Pericyte-Mediated Tissue Repair through PDGFRβ Promotes Peri-Infarct Astrogliosis, Oligodendrogenesis, and Functional Recovery after Acute Ischemic Stroke

“…Postoperative tests were performed three times with an interval of 10 min between attempts. The mNSS was performed as described previously (Yukami et al, 2015). Neurological function was graded on a scale of 0 to 14 (normal score, 0; maximal deficit score, 14).…”

Collateral Circulation in Ischemic Stroke

“…6770 In the field of neurosurgery, emergent bypass surgery has been applied for patients with acute ischemic stroke. 7172 Application of nitric oxide, 73 albumin, 74 and tumor necrosis factor-α inhibitor 75 has been shown to increase arteriogenesis (collateral formation from preexisting channels) in animal model of stroke. In addition, preclinical and clinical studies have showed that various pharmacological therapies may enhance angiogenesis (capillary formation from preexisting vessels) and vascuologenesis (de novo capillary formation), 677677 which includes sildenafil and phosphodiesterase type 5 inhibitors, 7879 erythropoietin/trophic factors, 808182 and statins with or without cell therapy.…”

Research of expression quantity of serum miR-146a and miR-146b in patients with acute cerebral infarction before and after the intervention of rosuvastatin

“…And the inflammatory response mediated by them plays an important role on the damage process of neurological function after cerebral infarction [21]. TNF-α can directly cause the inflammatory injury on neuron and gliocyte, which has also the chemotaxis of inflammatory cell [22]. IL-1β and IL-17 have toxic effect on neuron and gliocyte around the infarction focus, and they can lead to the cellular damage and necrocytosis [23,24].…”