Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke - PubMed (original) (raw)

Review

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

Xiaoming Hu et al. Circ Res. 2017.

Abstract

The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury after ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in blood-brain barrier integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events.

Keywords: blood-brain barrier; cerebrovascular circulation; endothelium; inflammation; pericytes; risk factors.

© 2017 American Heart Association, Inc.

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Figures

Figure 1

Figure 1. Risk factors and end-organ effects of vascular disease

Schematic illustration of leading risk factors for large and small vessel disease and stroke as well as key changes in vascular function, the BBB, atherosclerosis, and vascular structure. The lower portion of the figure illustrates progression vascular disease over time with major end-organ effects.

Figure 2

Figure 2. Mechanisms regulating function of eNOS and its impact

Activity of eNOS is increased in response to receptor- and shear stress-mediated effects. Activation of transient receptor potential V4 channels (TRPV4) is involved for some stimuli. Enzyme activity is dependent on L-arginine, calcium (Ca2+), calmodulin (CaM), and tetrahydrobiopterin (BH4) and is inhibited by caveolin-1. eNOS-mediated effects in healthy endothelium is show in the upper right. The bottom of the figure highlights major mechanisms that contribute to endothelial dysfunction, including the RAAS, oxidative stress, asymmetric dimethylarginine (ADMA), and Rho kinase. See text for additional details. Aldo, aldosterone; AT1R, AT1 receptor; Mito, mitochondria; ONOO−, peroxynitrite; O2−, superoxide; GPx, glutathione peroxidase; DDAH, dimethylarginine dimethylaminohydrolase (DDAH); ET1R, endothelin-1 receptor.

Figure 3

Figure 3. Changes in vascular structure and mechanics

Major structural and mechanical changes in the vasculature (shown in cross-section) that collectively reduce the vascular lumen, affect vasodilator responses, and limit vasodilator reserve (increase minimal vascular resistance). Physiological consequences of these changes are listed on the bottom.

Figure 4

Figure 4. The structural alterations in endothelial cells are critical for BBB opening early after ischemic stroke

A. The opening of paracellular pathways: cytoskeletal rearrangements and related signaling in endothelial cells. B. The transcellular pathway of BBB leakage. ADF: actin-depolymerizing factor; CaM: calmodulin; LIMK: LIM kinase; MLC: myosin light chain; MLCK: MLC kinase; MLCP: MLC phosphatase; MMP: matrix metallopeptidase; ROCK: Rho kinase TESK1: testicular protein kinase 1.

Figure 5

Figure 5. Pericytes play multifaceted roles in ischemia and reperfusion

Pericytes display both beneficial and detrimental functions during ischemia and reperfusion phases, and contribute significantly to the BBB damage and repair. 1) Pericyte contraction and dilation regulate cerebral blood flow in the ischemic and peri-lesion areas. 2) Pericyte protects other NVU components through releasing protective/trophic factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF), angiopoietin (Ang-1) and glial cell line-derived neurotrophic factor (GDNF). 3) Phagocytotic pericytes help to eliminate dead or injured tissue in the ischemic core, which in turn mitigates local inflammation and reduce secondary tissue damage. 4) Pericyte-endothelial cell interaction promotes angiogenesis after stroke. 5) Pericytes have the potential to serve as an origin of NVU components during tissue repair after ischemic stroke.

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