The current findings provide pioneering evidence in support of the fact that CGRP and high-intensity interval training increase VEGF and mTORC2 mRNA levels in the hippocampus of healthy male rats. Additionally, our research establishes that HIIT enhances cell proliferation, possibly via CGRP signaling. Specifically, our findings indicate that 1) exercise training can enhance VEGF and mTORC2 expression in brain tissue and 2) CGRP and mTORC2 may interact in the hippocampus.
Similar to the present study, Lu et al. measured the effect of eight weeks of intense exercise intervention higher than lactate threshold on VEGF levels in the brain tissue of C57BL/6 rats (22). They discovered an increase in VEGF mRNA levels. Lactate generated by muscles appears to enter the brain via MCT (monocarboxylate transporters), where it amplifies VEGF mRNA expression in brain tissue (22). In this context, it has been demonstrated that CGRP secretion is directly associated with lactate generation and linearly related to lactate release during hypoxic exercise. Given that CGRP is positively linked with VEGF release, acute exercise may cause an increase in VEGF content by raising CGRP (30, 31). Rezaei and Nourshahi’s experiments also revealed the usefulness of reducing the rate of brain stroke related to higher VEGF levels in the brain tissue of male Wistar rats (32). When exposed to anoxia, high-intensity intermittent exercise may decrease cerebral blood flow, reduce oxygenation and delivery to the brain, and considerably increase VEGF expression. This contributes to brain recovery following a stroke (10). Increased blood-brain barrier permeability is another stimulus, as demonstrated in a study by Cotman et al., where VEGF increased in the periphery crossed the blood-brain barrier and entered the brain, resulting in an increasing effect of cerebral VEGF (33). The inverse response of exercise intensity to VEGF expression (10) may be explained by the impact of high-intensity exercise on glucose uptake in the brain, as high-intensity exercise reduces glucose uptake in the brain (9). Collectively, the current findings demonstrate that part of the beneficial interventional effects of intensive intermittent exercise might be attributed to increased angiogenesis and neurogenesis in the hippocampus of healthy male rats via positive regulation of VEGF.
Despite this study’s increase in mTORC2 expression, certain mechanisms have been postulated to explain why mTORC2 function improves during intense intermittent exercise. Growth factor signals trigger this complex, and VEGF has been shown to activate several downstream pathways involved in angiogenesis, including the PI3K-Akt/mTORC2 pathway (34). When growth factor signals activate mTORC2, the increase in mTORC2 may be followed by an increase in VEGF due to intense activity. Additionally, exercise increases AKT phosphorylation in Ser473 in the dentate gyrus of the hippocampus (30). mTORC2 mediator has established the role of AKT ser473 phosphorylation (35). Therefore, mTORC2 may be directly related to AKT. In sum, mTORC2 integrates growth signals via a variety of mechanisms that regulate cell viability (36). The current work on CGRP inhibition and HIIT contradicts the studies by Mitsuaka et al. (2018) (37) and Burkham’s (2019) (14), which revealed that CGRP was directly involved in the production of VEGF by the endothelium because HIIT+CGRP inhibition on VEGF levels was accompanied with VEGF increase. This inconsistency is most likely owing to the fact that VEGF is produced by alternate routes, and it is expected that exercise-induced changes will be more pronounced on these pathways. However, the decrease in mTORC2 expression appears to increase VEGF expression, as Tian et al. (38) have shown. They demonstrated that CGRP inhibition had a negative effect on mTOR signaling in brain tissues, while these changes in FoxO3a (Forkhead box O3) levels were quite the opposite. Hence, the FoxO3a rise had a downtrend after CGRP injection. As a transcription factor, FoxO3a is affected by mTORC2 (39), which may be relevant to the expression of FoxO3a-suppressed VEGF (40). This is indeed not parallel with the present study findings. Interestingly, CGRP plays an important role in eliminating apoptosis and autophagy by activating Akt/mTORC2 signaling, which indicates cell proliferation and viability in brain tissue (39). In contrast to the increase in VEGF, it appears that the current study’s absence of mTORC2 increase can be detected in several stress-sensitive regions of the brain, including the hippocampus. As a result, forced treadmill running might be viewed as a source of stress generation (41).
There have been no studies to date that examine the concurrent effect of HIIT and CGRP inhibition on mTORC2 and VEGF levels in hippocampus tissue. However, this work demonstrated that inhibiting CGRP alters mTORC2 expression, implying a mediating role for CGRP in the process of mTORC2 production. Thus, in order to capture more precise cellular mechanisms, future research should include experimental studies on animal species and tissue types. The study’s primary limitation was the time period between animal sacrifices, as VEGF and mTORC2 are time-dependent.