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.

Due to the complex pathogenesis of acute ischemic stroke (AIS), further investigation into its underlying mechanisms is necessary. Presently, existing literature indicates a close association between ferroptosis and AIS injury; however, the precise mechanism and molecular target of ferroptosis in AIS injury remain elusive. By RNA sequencing, we found a significant increase in LCN2 expression in the ischemic cortex. In order to investigate the potential role of LCN2 in modulating AIS injury through the regulation of ferroptosis, we utilized RNA interference (RNAi) knockdown and gene overexpression experiments. The findings from experiments conducted both in vitro and in vivo revealed a marked increase in ferroptosis levels within the AIS model group. Suppression of the LCN2 gene resulted in a significant reduction in ferroptosis levels in OGD/R cells. Conversely, upregulation of LCN2 exacerbated ferroptosis levels in OGD/R cells. The results suggest that elevated levels of ferroptosis may result from heightened expression of LCN2, thereby exacerbating ischemia/reperfusion injury. This study indicates the involvement of ferroptosis in the pathogenesis of AIS and highlights LCN2 as a regulator of ferroptosis in AIS-induced injury, suggesting a potential therapeutic target for ischemic stroke.

BACKGROUND:MicroRNAs (miRNAs) are implicated in the progression of ischemic stroke (IS) and bone marrow-derived mesenchymal stem cells (BMSCs)-derived exosomes play a role in IS therapy. Herein we hypothesized that the BMSCs-derived exosomes containing overexpressed miR-138-5p could protect the astrocytes following IS involved with lipocalin 2 (LCN2). METHODS:The differentially expressed gene related to IS was initially identified by bioinformatics analysis. miR-138-5p was predicted to regulate LCN2. The expression of miR-138-5p and LCN2 was altered in the oxygen-glucose deprivation (OGD)-induced astrocytes. Furthermore, the cell behaviors and inflammatory responses were evaluated both in astrocytes alone and astrocytes co-cultured with exosomes derived from BMSCs overexpressing miR-138-5p to explore the involvement of miR-138-5p and LCN2 in IS. Besides, middle cerebral artery occlusion (MCAO) mouse model was established to explore the effect of BMSCs-derived exosomal miR-138-5p in IS in vivo. RESULTS:LCN2 was highly expressed in IS. Besides, LCN2 was a target gene of miR-138-5p. BMSCs-derived exosomes could be endocytosed by astrocytes via co-culture. Overexpression of miR-138-5p promoted the proliferation and inhibited apoptosis of astrocytes injured by OGD, accompanied by the reduced expression of inflammatory factors, which was achieved by down-regulating LCN2. More importantly, BMSCs delivered miR-138-5p to the astrocytes via exosomes and BMSCs-derived exosomal miR-138-5p alleviated neuron injury in IS mice. CONCLUSION:BMSCs-derived exosomal miR-138-5p reduces neurological impairment by promoting proliferation and inhibiting inflammatory responses of astrocytes following IS by targeting LCN2, which may provide a novel target for IS treatment.

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3'UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.

While inhibiting pathological angiogenesis has been long associated with the field of oncology, recent advances in angiogenesis research have impacted the progress of disease treatment for additional non-malignant diseases or chronic conditions in the fields of ophthalmology, cardiology, and gynecology. Moreover, stimulators of angiogenesis find application in ischemic diseases, while inhibitors of angiogenesis are being used to limit blood vessel formation, but in judicious ways that modify or "reprogram" the vasculature as a reinforcement for immunotherapy. We have noticed an increasing impact, as evidenced by increases in the total number of citations, in the literature surrounding the angiogenesis field suggesting that targeting angiogenesis per se is well established as a tractable approach for therapy in diverse conditions.

Angiogenesis inhibitors for the treatment of cancer have now been approved by the Food and Drug Administration in the United States, and in 28 other countries including China. Clinical application of this new class of drugs is informed by certain principles from angiogenesis research. Oncogenic mutations initiate tumorigenesis, but angiogenesis is necessary for expansion of tumor mass. Two angiogenesis inhibitors have been developed that have a broad spectrum of anticancer activity, yet virtually no side effects. Endogenous angiogenesis inhibitors act as tumor suppressor proteins. The angiogenic response in vivo is based on the genetic background of the host. Several types of angiogenesis inhibitors reveal a biphasic, U-shaped curve of efficacy. "Antiangiogenic chemotherapy" is a novel approach to the treatment of drug resistance.