Assessment of endothelial function in leptomeningeal arterioles derived from patients with Alzheimer's disease and vascular cognitive impairment.
Assessment of endothelial function in leptomeningeal arterioles derived from patients with Alzheimer's disease and vascular cognitive impairment.
复制标题
评估阿尔茨海默病和血管性认知障碍患者的软脑膜小动脉的内皮功能。
DOI：
10.1152/ajpheart.00367.2018
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Ungvari,Zoltan
中科院分区：
文献类型：
--
作者：
Toth,Peter;Tarantini,Stefano;Rutkai,Ibolya;Ungvari,Zoltan
Increasing evidence suggests that aging and pathological conditions associated with 33 accelerated cerebrovascular aging (eg hypertension, diabetes mellitus, obesity) induce 34 multifaceted impairment in microvascular function and dysregulation of cerebral blood flow, 35 which play a critical role in development of cognitive impairment (3, 10)(Figure 1). Vascular 36 contributions to cognitive impairment and dementia (VCID) are clinically highly significant as 37 they are potentially partially or completely reversible and/or preventable and represent potential 38 novel targets for intervention. 39In addition to the putative role of functional changes in neurons, astrocytes, pericytes and 40 microglia altering the release of vasoactive factors, dysfunction of the cerebrovascular 41 endothelium has been shown to play a central role in dysregulation of cerebral blood flow in 42 aging and age-related pathophysiological conditions (10). Endothelial cells are ideally positioned 43 to control vascular resistance, since they are in direct contact with the flowing blood and are 44 indirectly affected by factors released from cells of the neurovascular unit (astrocytes, smooth 45 muscle cells, pericytes and neurons). Endothelial cells contribute to the regulation of basal tone 46 of cerebral resistance vessels and basal cerebral perfusion via sensing and responding to changes 47 in hemodynamic forces, such as shear stress with the production of vasoactive substances, such 48 as nitric oxide. In addition, endothelial cells in intraparenchymal arterioles have been proposed 49 to contribute to the functional hyperemic response in the brain, mediating neuronal activation-50 induced increase in local blood flow, and to participate in the conducted upstream dilation of 51 arterioles feeding the given active neuronal area (1)(Figure 1). Strong evidence suggests that 52 aging and pathological conditions associated with accelerated cerebrovascular aging results in 53 endothelial dysfunction of cerebral arteries and arterioles both in animal models and in human 54 patients (10). Furthermore, dysregulation of cerebral blood flow and/or endothelial dysfunction 55 have/has been demonstrated both in patients suffering from Alzheimer’s disease and in animal 56 models of the disease (10). Up-regulation of NADPH-derived ROS production and mitochondrial 57 oxidative stress have been proposed to contribute to the endothelial dysfunction in these 58 pathological conditions individually or concurrently (8). Endothelial dysfunction is thought lead 59 to impaired neurovascular coupling/functional hyperemia, and chronic hypoperfusion of cerebral 60 tissue, resulting in compromised oxygen and nutrient delivery and washout of toxic by-products, 61 which likely impair neuronal function (Figure 1). Indeed, there is increasing preclinical evidence 62 that endothelial dysfunction in the cerebral circulation is causally related to cognitive 63 impairment (8). Several studies have demonstrated impaired cognitive function using animal 64 models with compromised endothelial function via pharmacological inhibition (7) or genetic 65 depletion of eNOS. The available evidence from clinical studies supports the view that healthy 66 endothelial function is important for the preservation of cognitive health in humans, too. 67 Endothelial dysfunction is a generalized condition and clinical studies demonstrate an 68 association between endothelial dysfunction assessed by flow-mediated dilation of the brachial 69 artery and mild cognitive impairment (11). Biomarkers of endothelial dysfunction have been 70 found to be related to reduced information processing speed and executive functioning in older 71 patients (2 …
Increasing evidence suggests that aging and pathological conditions associated with 33 accelerated cerebrovascular aging (eg hypertension, diabetes mellitus, obesity) induce 34 multifaceted impairment in microvascular function and dysregulation of cerebral blood flow, 35 which play a critical role in development of cognitive impairment (3, 10)(Figure 1). Vascular 36 contributions to cognitive impairment and dementia (VCID) are clinically highly significant as 37 they are potentially partially or completely reversible and/or preventable and represent potential 38 novel targets for intervention. 39In addition to the putative role of functional changes in neurons, astrocytes, pericytes and 40 microglia altering the release of vasoactive factors, dysfunction of the cerebrovascular 41 endothelium has been shown to play a central role in dysregulation of cerebral blood flow in 42 aging and age-related pathophysiological conditions (10). Endothelial cells are ideally positioned 43 to control vascular resistance, since they are in direct contact with the flowing blood and are 44 indirectly affected by factors released from cells of the neurovascular unit (astrocytes, smooth 45 muscle cells, pericytes and neurons). Endothelial cells contribute to the regulation of basal tone 46 of cerebral resistance vessels and basal cerebral perfusion via sensing and responding to changes 47 in hemodynamic forces, such as shear stress with the production of vasoactive substances, such 48 as nitric oxide. In addition, endothelial cells in intraparenchymal arterioles have been proposed 49 to contribute to the functional hyperemic response in the brain, mediating neuronal activation-50 induced increase in local blood flow, and to participate in the conducted upstream dilation of 51 arterioles feeding the given active neuronal area (1)(Figure 1). Strong evidence suggests that 52 aging and pathological conditions associated with accelerated cerebrovascular aging results in 53 endothelial dysfunction of cerebral arteries and arterioles both in animal models and in human 54 patients (10). Furthermore, dysregulation of cerebral blood flow and/or endothelial dysfunction 55 have/has been demonstrated both in patients suffering from Alzheimer’s disease and in animal 56 models of the disease (10). Up-regulation of NADPH-derived ROS production and mitochondrial 57 oxidative stress have been proposed to contribute to the endothelial dysfunction in these 58 pathological conditions individually or concurrently (8). Endothelial dysfunction is thought lead 59 to impaired neurovascular coupling/functional hyperemia, and chronic hypoperfusion of cerebral 60 tissue, resulting in compromised oxygen and nutrient delivery and washout of toxic by-products, 61 which likely impair neuronal function (Figure 1). Indeed, there is increasing preclinical evidence 62 that endothelial dysfunction in the cerebral circulation is causally related to cognitive 63 impairment (8). Several studies have demonstrated impaired cognitive function using animal 64 models with compromised endothelial function via pharmacological inhibition (7) or genetic 65 depletion of eNOS. The available evidence from clinical studies supports the view that healthy 66 endothelial function is important for the preservation of cognitive health in humans, too. 67 Endothelial dysfunction is a generalized condition and clinical studies demonstrate an 68 association between endothelial dysfunction assessed by flow-mediated dilation of the brachial 69 artery and mild cognitive impairment (11). Biomarkers of endothelial dysfunction have been 70 found to be related to reduced information processing speed and executive functioning in older 71 patients (2 …