Vascular remodeling after ischemic stroke: Mechanisms and therapeutic potentials

Abstract

The brain vasculature has been increasingly recognized as a key player that directs brain development, regulates homeostasis, and contributes to pathological processes. Following ischemic stroke, the reduction of blood flow elicits a cascade of changes and leads to vascular remodeling. However, the temporal profile of vascular changes after stroke is not well understood. Growing evidence suggests that the early phase of cerebral blood volume (CBV) increase is likely due to the improvement in collateral flow, also known as arteriogenesis, whereas the late phase of CBV increase is attributed to the surge of angiogenesis. Arteriogenesis is triggered by shear fluid stress followed by activation of endothelium and inflammatory processes, while angiogenesis induces a number of pro-angiogenic factors and circulating endothelial progenitor cells (EPCs). The status of collaterals in acute stroke has been shown to have several prognostic implications, while the causal relationship between angiogenesis and improved functional recovery has yet to be established in patients. A number of interventions aimed at enhancing cerebral blood flow including increasing collateral recruitment are under clinical investigation. Transplantation of EPCs to improve angiogenesis is also underway. Knowledge in the underlying physiological mechanisms for improved arteriogenesis and angiogenesis shall lead to more effective therapies for ischemic stroke.

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…GDF10 signals through TGF-βRI and II and Smad 2/3, to activate PI3 kinase gene systems and to inhibit the signaling of phosphatase and tensin homolog and suppressor of cytokine signaling 3. These gene systems mediate axonal sprouting in other contexts in the adult, such as in optic nerve and spinal cord injury [99][100][101]. These data indicate that GDF10 is one molecule in a trigger after stroke and coordinately activates parallel growth promotion cascades.…”

Herbal Formula Danggui-Shaoyao-San Promotes Neurogenesis and Angiogenesis in Rat Following Middle Cerebral Artery Occlusion

“…Conditions that promote focal angiogenesis and neurogenesis improve outcome of stroke via promoting functional recovery [3,5]. To date, several reports showed that Chinese herbal compounds and individual herbs could promote neurogenesis and angiogenesis in cerebral ischemia models and could improve neural functional reconstruction and restoration [32][33][34].…”

“…Angiogenesis, the generation of new blood vessels, is most prominent in the ischemic boundary zone and is correlated with reduced injury in animal models and human stroke patients [3,4]. Accumulating experimental studies showed that promoting post-ischemic angiogenesis and neurogenesis can improve neurological function [5,6], suggesting it is a promising therapeutic target for ischemic stroke.…”

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

“…For example, few studies have suggested a relationship between cerebral ischemia and PPARα/RXRα Activation, as the function of this pathway involves lipid degradation and obesity [43] . In the JU group, 6 of the top 10 core pathways (Acute Myeloid Leukemia Signaling, Melatonin Signaling, FGF Signaling, Amyotrophic Lateral Sclerosis Signaling, Neuropathic Pain Signaling in Dorsal Horn Neurons, and Synaptic Long Term Potentiation) are widely accepted as involved in neuronal systems [44][45][46][47][48][49] . The other 4 of the top 10 core pathways (Molecular Mechanisms of Cancer, CD27 Signaling in Lymphocytes, Cardiac Hypertrophy Signaling, and Cholecystokinin Gastrin-mediated Signaling) showed no clear evidence of their association with cerebral ischemia [50,51] .…”