Chronic cocaine induces HIF-VEGF pathway activation along with angiogenesis in the brain

Abstract

Cocaine induces vasoconstriction in cerebral vessels, which with repeated use can result in transient ischemic attacks and cerebral strokes. However, the neuroadaptations that follow cocaine’s vasoconstricting effects are not well understood. Here, we investigated the effects of chronic cocaine exposure (2 and 4 weeks) on markers of vascular function and morphology in the rat brain. For this purpose we measured nitric oxide (NO) concentration in plasma, brain neuronal nitric oxide synthase (nNOS or NOS1), HIF-1α, and VEGF expression in different brain regions, i.e., middle prefrontal cortex, somatosensory cortex, nucleus accumbens, and dorsal striatum, using ELISA or Western blot. Additionally, microvascular density in these brain regions was measured using immunofluorescence microscopy. We showed that chronic cocaine significantly affected NOS1, HIF-1α and VEGF expression, in a region- and cocaine treatment-time- dependent manner. Cerebral microvascular density increased significantly in parallel to these neurochemical changes. Furthermore, significant correlations were detected between VEGF expression and microvascular density in cortical regions (middle prefrontal cortex and somatosensory cortex), but not in striatal regions (nucleus accumbens and dorsal striatum). These results suggest that following chronic cocaine use, as cerebral ischemia developed, NOS1, the regulatory protein to counteract blood vessel constriction, was upregulated; meanwhile, the HIF-VEGF pathway was activated to increase microvascular density (i.e., angiogenesis) and thus restore local blood flow and oxygen supply. These physiological responses were triggered presumably as an adaptation to minimize ischemic injury caused by cocaine. Therefore, effectively promoting such physiological responses may provide novel and effective therapeutic solutions to treat cocaine-induced cerebral ischemia and stroke.

X‐box binding protein l splicing attenuates brain microvascular endothelial cell damage induced by oxygen‐glucose deprivation through the activation of phosphoinositide 3‐kinase/protein kinase B, extracellular signal‐regulated kinases, and hypoxia‐inducible factor‐1α/vascular endothelial growth factor signaling pathways

“…Furthermore, mounting evidence has demonstrated that HIF1α/VEGF signaling pathways are essential for angiogenesis (Yen, Cho, & Kwon, 2017;Yin, Clare, Zhang, Volkow, & Du, 2017). Hypoxiaand ischemia-induced ERS promote the expression of VEGF-A and induce angiogenesis (Zeng et al, 2013).…”

Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1α Protein

“…Baranova et al ( 2007 ) found that knockdown of neuronal HIF-1α enhances ischemic brain injury. Activation of HIF-1α-associated signaling cascades, such as EPO pathway (Liu et al, 2006 ; Ryou et al, 2012 ) and VEGF pathway (Yin W. et al, 2017 ) in neurons could protect the brain from I/R damage through increasing microvascular density and/or restoring local blood flow and oxygen supply. Yang X. S. et al ( 2017 ) found that HIF-1α involved in necroptosis contributed to ischemic brain injury induced by OGD and MCAO.…”

Batroxobin accelerated tissue repair via neutrophil extracellular trap regulation and defibrinogenation in a murine ischemic hindlimb model

“…Considering the decline in NETs providing a microthrombogenic platform in the acute phase, batroxobin might exacerbate microcirculation to a lesser extent, thereby escaping more severe hypoxia. Thus, the lower level of Hif-1α transcripts conceivably led to the downregulation of Vegf-a gene expression, as Hif-1α is a potent transcriptional factor of Vegf-a mRNA [51,52].…”