Combination of Vascular Endothelial and Fibroblast Growth Factor 2 for Induction of Neurogenesis and Angiogenesis after Traumatic Brain Injury

Abstract

Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) are potent mitogens for endogenous neural stem cells (eNSC) and also induce angiogenesis. We infused the individual factors or their combination into the lateral ventricles of mice for 7 days after traumatic brain injury (TBI) in order to evaluate the effects on functional outcome and on eNSC proliferation and differentiation. The results show that VEGF induced a significant increment in the number of proliferating eNSC in the subventricular zone and in the perilesion cortex and that combination of FGF2 and VEGF did not augment the effects of VEGF alone. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia while only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF, FGF2, or their combination as compared to vehicle. Injury size was significantly reduced only in mice treated with VEGF suggesting additional neuroprotective effects for VEGF. Combination therapy did not have an additive effect on outcome or neuronal differentiation. In conclusion, FGF2-VEGF combination does not augment neurogenesis and angiogenesis or reduce lesion volumes after TBI compared with individual factors. This may suggest the existence of a ceiling effect for brain regeneration.

Lipoic acid and bone marrow derived cells therapy induce angiogenesis and cell proliferation after focal brain injury

“…Another essential point concerning recovery therapy after focal brain injury is the angiogenesis, which seems to be stimulated and accelerated by treatment with antioxidant and neuroprotective factors after brain damage [21,95,96]. It is important to remark that angiogenesis is directly related to neurogenesis and neuroregeneration since blood supply is necessary for new neuronal survival and development [97,98].…”

VEGF reverts the cognitive impairment induced by a focal traumatic brain injury during the development of rats raised under environmental enrichment

“…Whereas most studies to determine VEGF function in learning and memory used intracerebroventricular [8,38,39] or intrahippocampal administration [40], in our work, VEGF has been administered immediately anterior to the primary visual cortex and a direct arrival to the DG could be discarded. The visual cortex provides a crucial sensory input to the hippocampus and is a key component for the creation of visuospatial memories [41].…”

“…VEGF administration did not revert to the neuronal density in the primary visual cortex as both the PBS and VEGF-infused groups presented values similar to the standard-reared control group. It has been proposed that there is a ceiling effect of VEGF and FGF-2 for inducing changes on neurovascular components after injury [39]. This fact could explain that VEGF acts only if the studied parameters are lower than physiological values.…”

Fibroblast Growth Factor-2 Signaling in Neurogenesis and Neurodegeneration

“…Rats treated with ICV FGF2 immediately following TBI showed enhanced neurogenesis in the SVZ and SGZ at 1 and 4-weeks post TBI, increased numbers of surviving neurons, and improved cognitive function as compared to controls [44]. In another study, after mice were given TBI according to the CHI model, which recapitulates focal TBI resulting in isolated frontoparietal cortical injury, mice treated with continuous infusion of FGF2 to the lateral ventricles showed improved motor function, increased astrocytic proliferation and number of blood vessels in the perilesional cortex vs. control, and increased neuronal proliferation when FGF2 was given in combination with vascular endothelial growth factor (VEGF)[45]. …”