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

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.

可卡因可导致大脑血管收缩，反复使用可引发暂时性缺血性发作及脑卒中。然而，可卡因血管收缩作用后的神经适应性尚不明确。本研究旨在探讨慢性可卡因暴露（2周和4周）对大鼠脑部血管功能及形态学标记的影响。为此，我们通过ELISA或Western blot技术，测量了血浆中一氧化氮（NO）浓度、脑神经元一氧化氮合酶（nNOS或NOS1）、HIF-1α和VEGF在不同脑区（如前额叶皮层中部、体感皮层、伏隔核和背侧纹状体）的表达。此外，利用免疫荧光显微镜测量了这些脑区的微血管密度。结果显示，慢性可卡因显著影响NOS1、HIF-1α和VEGF的表达，且这种影响具有区域性和可卡因治疗时间依赖性。与这些神经化学变化平行，大脑微血管密度显著增加。此外，在皮层区域（前额叶皮层中部和体感皮层）中检测到VEGF表达与微血管密度之间的显著相关性，但在纹状体区域（伏隔核和背侧纹状体）中则未发现。这些结果表明，在慢性可卡因使用后，随着大脑缺血的发展，NOS1（一种调节蛋白，用于对抗血管收缩）的表达上调；同时，HIF-VEGF通路被激活，以增加微血管密度（即血管生成），从而恢复局部血流和氧气供应。这些生理反应可能作为一种适应性机制，以最小化由可卡因引起的缺血损伤。因此，有效促进此类生理反应可能为治疗可卡因诱导的大脑缺血和脑卒中提供新颖且有效的治疗策略。