Background
Ischemic stroke is a serious cerebrovascular disease with high morbidity and disability. Zinc accumulation has been shown to play a vital role in neuronal death and blood–brain barrier ...damage following ischemia in acute stage. However, almost nothing is known about whether zinc is involved in neurological recovery in ischemic prolonged period. This study investigates whether zinc promotes neurological recovery through astrocytes‐induced angiogenesis during ischemic repair phase.
Methods
Sprague–Dawley rats were subjected to 2 h ischemia/14, 21, and 28 days reperfusion by middle cerebral artery occlusion, then administered ZnCl2 (10 mg/kg) via intraperitoneally daily from 7 days to tissue collection to observe brain tissue morphology, neurological function recovery by cortical width index, Adhesive removal test, and Forelimb placing test. Angiogenesis, astrocyte activation, and HIF‐1α/VEGF pathway were assessed via Western blot, immunofluorescence, and BrdU method in vivo and in vitro.
Results
The results showed that zinc significantly alleviated brain atrophy and improved neurological function recovery during the cerebral ischemia repair stage. Zinc significantly increased the protein levels of HIF‐1α, VEGF‐A, and VEGF‐R2 in astrocytes, and promoted angiogenesis during cerebral ischemia repair. In vitro and in vivo studies confirmed that zinc promoted angiogenesis via the astrocyte‐mediated HIF‐1α/VEGF signaling pathway.
Conclusions
Zinc significantly improves neurological function recovery during the cerebral ischemia repair stage, providing new evidence supporting zinc as a potential therapeutic target for ischemic stroke by promoting astrocyte induced angiogenesis.
Zinc can alleviate cerebral ischemia atrophy and promote neurological function recovery during cerebral ischemia repair stage.
Zinc promoted angiogenesis via astrocyte‐mediated HIF‐1α/VEGF signaling pathway.
Zinc may serve as a potential therapeutic target for the treatment of functional.
During tumor development, the tumor itself must continuously generate new blood vessels to meet their growth needs while also allowing for tumor invasion and metastasis. One of the most common ...features of tumors is hypoxia, which drives the process of tumor angiogenesis by regulating the tumor microenvironment, thus adversely affecting the prognosis of patients. In addition, to overcome unsuitable environments for growth, such as hypoxia, nutrient deficiency, hyperacidity, and immunosuppression, the tumor microenvironment (TME) coordinates angiogenesis in several ways to restore the supply of oxygen and nutrients and to remove metabolic wastes. A growing body of research suggests that tumor angiogenesis and hypoxia interact through a complex interplay of crosstalk, which is inextricably linked to the TME. Here, we review the TME's positive contribution to angiogenesis from an angiogenesis-centric perspective while considering the objective impact of hypoxic phenotypes and the status and limitations of current angiogenic therapies.
Display omitted
•A close interactive link exists between tumor angiogenesis, hypoxia, and TME, collectively promoting tumorigenesis and progression.•Growth factors in the tumor microenvironment are secreted and regulated by various cell types, and a significant correlation exists between their expression levels and hypoxia.•The development of anti-angiogenic therapy is hampered by the lack of accurate biomarkers, the uncertain time window of medication, and the widespread problem of drug resistance.
The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been shown to play major roles not only in physiological but also in most pathological angiogenesis, such as cancer. VEGF ...belongs to the PDGF supergene family characterized by 8 conserved cysteines and functions as a homodimer structure. VEGF-A regulates angiogenesis and vascular permeability by activating 2 receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk1 in mice). On the other hand, VEGF-C/VEGF-D and their receptor, VEGFR-3 (Flt-4), mainly regulate lymphangiogenesis. The VEGF family includes other interesting variants, one of which is the virally encoded VEGF-E and another is specifically expressed in the venom of the habu snake (Trimeresurus flavoviridis). VEGFRs are distantly related to the PDGFR family; however, they are unique with respect to their structure and signaling system. Unlike members of the PDGFR family that strongly stimulate the PI3K-Akt pathway toward cell proliferation, VEGFR-2, the major signal transducer for angiogenesis, preferentially utilizes the PLCγ-PKC-MAPK pathway for signaling. The VEGF-VEGFR system is an important target for anti-angiogenic therapy in cancer and is also an attractive system for pro-angiogenic therapy in the treatment of neuronal degeneration and ischemic diseases.
Tumor growth and metastasis rely on tumor vascular network for the adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex program of growth factor signaling, ...endothelial cell (EC) proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. Numerous pro-angiogenic drivers have been identified, the most important of which is the vascular endothelial growth factor (VEGF). The importance of pro-angiogenic inducers in tumor growth, invasion and extravasation make them an excellent therapeutic target in several types of cancers. Hence, the number of anti-angiogenic agents developed for cancer treatment has risen over the past decade, with at least eighty drugs being investigated in preclinical studies and phase I-III clinical trials. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the inhibition of receptor tyrosine kinase (RTK) enzymes. Despite promising preclinical results, anti-angiogenic monotherapies led only to mild clinical benefits. The minimal benefits could be secondary to primary or acquired resistance, through the activation of alternative mechanisms that sustain tumor vascularization and growth. Mechanisms of resistance are categorized into VEGF-dependent alterations, non-VEGF pathways and stromal cell interactions. Thus, complementary approaches such as the combination of these inhibitors with agents targeting alternative mechanisms of blood vessel formation are urgently needed. This review provides an updated overview on the pathophysiology of angiogenesis during tumor growth. It also sheds light on the different pro-angiogenic and anti-angiogenic agents that have been developed to date. Finally, it highlights the preclinical evidence for mechanisms of angiogenic resistance and suggests novel therapeutic approaches that might be exploited with the ultimate aim of overcoming resistance and improving clinical outcomes for patients with cancer.
PDF
