Overexpression of adiponectin promotes focal angiogenesis in the mouse brain following middle cerebral artery occlusion

Abstract

Recent studies indicate that overexpression of adiponectin (APN) could attenuate ischemic brain injury. However, the mechanism of APN effect remains unclear. In this study, we investigated the cellular mechanisms of APN action during cerebral ischemia. Adult mice (n=120) received an intracerebral injection of adeno-associated viral vector carrying the APN gene (AAV-APN). The mice were subjected to a transient ispilateral middle cerebral artery occlusion (tMCAO) after 7-day AAV-APN gene transfer. Cortical atrophy volume, neurological function, microvessels counts, phospho-AMPK and downstream angiogenic factor vascular endothelial growth factor (VEGF) were examined. Overexpression of APN was observed in the mouse brain following AAV-APN gene transfer. Cortical atrophy volume was attenuated in the AAV-APN-transduced mice compared with the AAV-GFP and saline-treated mice (7.9 ± 0.6%, 19.8 ± 0.3% and 20.3 ± 1.1%, respectively, P<0.05), with significant improvement in neurological function and an increased number of microvessels (199 ± 5 vs 151 ± 4 and 148 ± 4 mm(-2), P<0.01). Furthermore, the expression of phospho-AMPK and VEGF were increased in the AAV-APN-transduced compared with the control mice (P<0.01), whereas inhibiting phospho-AMPK, reducing VEGF expression and attenuating the effect of APN on brain atrophy and angiogenesis (P<0.01). APN overexpression attenuates ischemia-induced brain atrophy and has improvement in neurological function. The consequence is related to promotion of focal angiogenesis. The AMPK signaling pathway has an important role in upregulating angiogenic factor VEGF.

The emerging role of adiponectin in cerebrovascular and neurodegenerative diseases

“…Among the subtypes of cerebral ischemia, intracranial atherosclerosis is associated with lower adiponectin levels than other ischemic stroke subtypes [47][48][49]. Thus, atherosclerotic plaques may serve as a central mediator of the neuroprotective effects of adiponectin, including its anti-inflammatory and angiogenic activities, suggesting an association of adiponectin with neurologic disorders [42,52] (Fig. 2).…”

“…The adiponectin receptor levels are reduced in mouse diabetic models, particularly in skeletal muscle and adipose tissue [40,41]. Recent focus has been directed toward adiponectin signaling regulation in the brain [42,43].…”

“…Chen et al [52] demonstrated that APN displays potent cerebroprotective activity via an anti-inflammatory effect and that NF-κB is a key component in this process. Employing a mouse model of transient unilateral middle cerebral artery occlusion (tMCAO), Shen et al demonstrated that adiponectin overexpression attenuates ischemia-induced brain atrophy and improves neurological function secondary to augmented focal angiogenesis [42]. Furthermore, the AMPK signaling pathway plays an important role in the upregulation of the angiogenic factor VEGF.…”

Association between Risk Factors for Vascular Dementia and Adiponectin

“…Adiponectin reduced the infarct size through nitric oxide synthase dependent mechanism in cerebral ischemic stroke mice model [209, 210]. In addition, adiponectin activates AMPK phosphorylation in cerebral ischemic stroke mice model [211]. Then, the activation of VEGF by the activated AMPK signaling promotes angiogenesis in cerebral ischemic brain [212, 213].…”

Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology

“…Low circulating adiponectin levels have been associated with increased mortality after ischemic stroke and may even help to predict neurological severity and functional outcome [108,109]. In a focal cerebral ischemia model in mice, the overexpression of adiponectin ameliorated the ischemia-induced brain atrophy and improved overall neurological function, effects associated with enhanced angiogenesis [110]. There is also evidence that adiponectin can have protective effects against ischemic insults through endothelial nitric oxide synthase-dependent hemodynamic mechanisms and/or anti-inflammatory effects through the NF-κB pathway [111,112].…”