Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery

Although microvascular dysfunction accompanies cognitive decline in aging, vascular dementia, and Alzheimer's disease, tools to study microvasculature longitudinally in vivo are lacking. Here, we use Doppler optical coherence tomography (OCT) and angiography for noninvasive, longitudinal imaging of mice with chronic cerebral hypoperfusion for up to 1 month. In particular, we optimized the OCT angiography method to selectively image red blood cell (RBC)-perfused capillaries, leading to a novel way of assessing capillary supply heterogeneity in vivo. After bilateral common carotid artery stenosis (BCAS), cortical blood flow measured by Doppler OCT dropped to half of baseline throughout the imaged tissue acutely. Microscopic imaging of the capillary bed with OCT angiography further revealed local heterogeneities in cortical flow supply during hypoperfusion. The number of RBC-perfused capillaries decreased, leading to increased oxygen diffusion distances in the days immediately after BCAS. Linear regression showed that RBC-perfused capillary density declined by 0.3% for a drop in flow of 1 mL/100 g per minute, and decreases in RBC-perfused capillary density as high as 25% were observed. Taken together, these results demonstrate the existence of local supply heterogeneity at the capillary level even at nonischemic global flow levels, and demonstrate a novel imaging method to assess this heterogeneity. Keywords: angiography; capillary recruitment; Doppler optical coherence tomography; hypoperfusion; vascular dementia INTRODUCTION Chronic cerebral hypoperfusion induced by small-artery occlusion or critical arterial stenosis is a pathophysiologic hallmark of vascular dementia. Histologically characterized by white matter changes and multifocal infarctions, chronic cerebral hypoperfusion is associated with cognitive decline. 1-3 Rodent models of chronic cerebral hypoperfusion that use common carotid artery stenosis or occlusion mimic many aspects of vascular cognitive impairment in patients, including decreased cerebral blood flow, inflammation and blood-brain barrier abnormalities, brain atrophy, white matter degeneration, decreased metabolism, as well as impaired working memory. 4 Bilateral common carotid artery occlusion has been widely used in the rat to model chronic cerebral hypoperfusion. 5 Recently, mouse bilateral common carotid artery stenosis (BCAS) models have emerged. 6 In these models, although the degree of hypoperfusion is correlated with the extent of ischemic lesions and neurologic impairment, 7 the magnitude of flow reductions after BCAS were moderate at best (~30 to 40%), 8 at least relative to classic ischemic thresholds of 80 to 85%, 9-11 and lasted only a few days before collateral development and recovery of flow. The lack of classic ischemia raises questions about the precise mechanism of tissue loss and cognitive impairment. Previous studies have used laser Doppler Journal of Cerebral Blood

Section: Resultsmentioning

confidence: 99%

Micro-Heterogeneity of Flow in a Mouse Model of Chronic Cerebral Hypoperfusion Revealed by Longitudinal Doppler Optical Coherence Tomography and Angiography

Srinivasan

Radhakrishnan

et al. 2015

“…Compromised upstream conduction of NVC signals from PAs to the pial vasculature is an attractive potential mediator of the NVC deficits observed in hypertensive animals as conduction of vasodilation is impaired in SHR mesenteric arteries. 44 In addition, pericytes have been shown to be active regulators of capillary diameter 45,46 and contributors to NVC mechanisms 39 suggesting that impairments at the capillary level could also contribute to hypertension-induced cerebrovascular dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Parenchymal Arteriole Tone and Astrocyte Signaling Protect Neurovascular Coupling Mediated Parenchymal Arteriole Vasodilation in the Spontaneously Hypertensive Rat

Iddings

Kim

Zhou

et al. 2015

Functional hyperemia is the regional increase in cerebral blood flow upon increases in neuronal activity which ensures that the metabolic demands of the neurons are met. Hypertension is known to impair the hyperemic response; however, the neurovascular coupling mechanisms by which this cerebrovascular dysfunction occurs have yet to be fully elucidated. To determine whether altered cortical parenchymal arteriole function or astrocyte signaling contribute to blunted neurovascular coupling in hypertension, we measured parenchymal arteriole reactivity and vascular smooth muscle cell Ca 2+ dynamics in cortical brain slices from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. We found that vasoconstriction in response to the thromboxane A 2 receptor agonist U46619 and basal vascular smooth muscle cell Ca 2+ oscillation frequency were significantly increased in parenchymal arterioles from SHR. In perfused and pressurized parenchymal arterioles, myogenic tone was significantly increased in SHR. Although K + -induced parenchymal arteriole dilations were similar in WKY and SHR, metabotropic glutamate receptor activation-induced parenchymal arteriole dilations were enhanced in SHR. Further, neuronal stimulation-evoked parenchymal arteriole dilations were similar in SHR and WKY. Our data indicate that neurovascular coupling is not impaired in SHR, at least at the level of the parenchymal arterioles. Keywords: astrocytes; brain slice; cerebral blood flow; hypertension; neurovascular coupling; parenchymal arterioles INTRODUCTION Functional hyperemia (FH), the process in which neuronal activation triggers local increases in cerebral blood flow (CBF), is of particular importance for cerebral homeostasis as it ensures that neuronal metabolic demands are met. 1 Despite recent controversy, 2,3 numerous in vitro and in vivo studies suggest that astrocytes act as intermediaries in the neurovascular coupling (NVC)-mediated vascular responses that govern the hyperemic response. Although NVC-mediated signaling can elicit both vasodilation and vasoconstriction, the focus of this study is to address NVC-mediated vasodilatory responses. During the orchestrated signaling among neurons, astrocytes, and the cerebral vasculature that occurs during NVC-mediated vasodilation, synaptically released glutamate binds to astrocytic metabotropic glutamate receptors (mGluR) increasing intracellular Ca 2+ , 1,4 which, in turn, results in the release of vasoactive signals such as arachidonic acid (AA) metabolites 4 and K + . 5 Although FH is impaired in hypertensive patients and animal models of hypertension, 6-9 the mechanisms by which hypertension disrupts NVC among cells in the neurovascular unit is not fully understood. A few elegantly designed studies, primarily evaluating pial arteriole function, have used regional CBF measurements to deliver valuable insight into the vascular mechanisms underlying NVC disruptions during acute, short-term Angiotensin II-induced hypertension 6,9 and chronic hypertension. 8 However,

“…14 The few studies that have addressed the response of PCs to cerebral ischemia have been limited to the acute phase. After ischemia, PC contraction might influence capillary patency, 15 while ultrastructural examinations suggest that PCs migrate to the injured parenchyma. 16 Recently, a novel subpopulation of mural cells has been described that shares with the PC the perivascular location and a common set of markers, including platelet-derived growth factor receptor beta (PDGFRb).…”

Section: Introductionmentioning

confidence: 99%

Early Loss of Pericytes and Perivascular Stromal Cell-Induced Scar Formation after Stroke

Fernández-Klett

Potas

Hilpert

et al. 2012

205

249

Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRb) þ and CD105 þ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRb þ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.