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Review
. 2023 Jul;44(7):1305-1321.
doi: 10.1038/s41401-023-01061-2. Epub 2023 Feb 24.

Angiogenesis after ischemic stroke

Jie Fang #  1 , Zhi Wang #  1 , Chao-Yu Miao  2
Affiliations
Review

Angiogenesis after ischemic stroke

Jie Fang et al. Acta Pharmacol Sin. 2023 Jul.

Abstract

Owing to its high disability and mortality rates, stroke has been the second leading cause of death worldwide. Since the pathological mechanisms of stroke are not fully understood, there are few clinical treatment strategies available with an exception of tissue plasminogen activator (tPA), the only FDA-approved drug for the treatment of ischemic stroke. Angiogenesis is an important protective mechanism that promotes neural regeneration and functional recovery during the pathophysiological process of stroke. Thus, inducing angiogenesis in the peri-infarct area could effectively improve hemodynamics, and promote vascular remodeling and recovery of neurovascular function after ischemic stroke. In this review, we summarize the cellular and molecular mechanisms affecting angiogenesis after cerebral ischemia registered in PubMed, and provide pro-angiogenic strategies for exploring the treatment of ischemic stroke, including endothelial progenitor cells, mesenchymal stem cells, growth factors, cytokines, non-coding RNAs, etc.

Keywords: angiogenesis; endothelial progenitor cells; ischemic stroke; secreted proteins; stem cells.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Schematics of key steps in angiogenesis after ischemic stroke.
a Pro-angiogenic molecules such as NO and VEGF induce local vasodilation, antagonize tight junctions between ECs, and initiate angiogenesis after ischemic stroke. Pericytes and smooth muscle cells are also loosened, resulting in extravasation of intravascular plasma proteins. b Activated ECs (graded pink) are induced to proliferate and migrate by a variety of angiogenic factors (VEGF, FGF, PDGF, αvβ3 integrin, etc.) to form subulate vascular buds. c Stimulated by VEGF, integrins (αvβ3 or α5) and other factors, activated EC continue to proliferate and migrate outwards, forming lumen with adjacent budding. d The newly formed lumen is not stable and needs to ensure endothelial cell survival and function, for example, tight junctions between ECs, orderly support of pericytes and smooth muscle cells, and deposition of the extracellular matrix.
Fig. 2
Fig. 2. Major stem cell therapies and its mechanisms for ischemic stroke.
After stroke, the administered stem cells arrived the peri-infarct area and not only replaced the injured cells by directly differentiating into the corresponding ECs, neural cells, etc., but also promoted angiogenesis in the ischemic area through a variety of mechanisms. Endothelial progenitor cells could not only directly increase HIF-1α signaling and plasma VEGF levels, but also increase CD31 and VEGF expression by secreting exosomes in the brain. MSCs could promote angiogenesis in many ways, such as transferring their functional mitochondria to stroke-damaged ECs through nanotubes, and activating the PI3K/Akt/eNOS signaling pathway by secreting exosomes to up-regulate the expression of microRNAs and angiogenic factors. And the expression and release of endogenous angiogenic factors such as VEGF/VEGFR, Ang-1/Tie-2 and EGF in the peri-infarct zone were also increased through Notch signaling. NPCs/NSCs and OPCs could promote angiogenesis by increasing tight junction proteins in brain capillaries through Ang-1/Tie2 and VEGF/VEGFR2 signaling pathways, and by promoting β-catenin in ECs through Wnt7a.
Fig. 3
Fig. 3. Major factors and signaling pathways of angiogenesis after cerebral ischemia. Ischemia or hypoxia resulting from cerebral ischemia increased VEGF expression by upregulating HIF-1α and 15-LO-1/15-HETE systems, and subsequently VEGF promoted pericyte coverage of ECs by increasing N-cadherin expression on brain capillaries.
NGF promoted angiogenesis by activating p-focal adhesion kinase (FAK) or PI3K/Akt signaling pathways after ischemic stroke, and similar pathways had also been found in TSLP and its receptor TSLPR. IL-1α, TNF-1α and SDF-1α also promoted angiogenesis by activating the expression of downstream genes through their receptors, respectively.
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