On VEGF and related factors in neurotrauma

At present, there is no cure for traumatic spinal cord and brain injuries. Therapies in use have only modest effect on outcome. Therefore, the need to better understand the biology of traumatic CNS injuries, making development of new therapies possible, is huge.

The interest in Vascular Endothelial Growth Factor (VEGF) in the Central Nervous System (CNS) is mulifactorial and has implications in neural and vascular pathophysiology, regeneration and protection. This study was undertaken to explore the eventual expression and possible function of VEGF, the VEGF receptors (VEGFR), the axon guidance molecules semaphorins and neuropilins and the transcription factor Hypoxia Inducible Factor (HIF) after different kind of traumatic injuries to the CNS.

In traumatic spinal cord injuries expression of VEGF and the VEGF receptors were found primarily in astrocytes and inflammatory cells. It was also noted that vessels positive for VEGF receptor markers were not always positive for markers of mature blood vessels with intact blood-brain barrier (BBB), indicating VEGF as important for angiogenesis and possibly BBB alterations. In addition, it was found that prostaglandins could upregulate VEGF expression after spinal microinjections in vivo and in spinal cord scar tissue in vitro.

Neuropilins (Np) are VEGF co-receptors that are also essential in the receptor complex for class 3 semaphorins (Sema3), axon guidance molecules that typically mediate axon growth repulsion. Sema3A, 3F, 4F, Np1 and Np2 were studied after intramedullary axotomy of rat lumbar spinal cord motoneurons, an injury model followed by motoneuron survival and regeneration. Sema3A was upregulated in motoneurons and the scar, Np2 in the motoneurons and Sema3F in the ventral roots at the injured side suggesting involvement of these factor in the injury response to intramedullary axotomy.

The expression of HIFs, molecules of importance for adaptation to hypoxia and major regualtors of VEGF expression, were studied after intramedullary axotomy to motoneurons. HIF1alpha but not HIF2alpha expression was found in injured motoneurons with a maximum expression after 7 days. VEGF expression was also found in injured motoneurons and motoneuron survival in vitro was increased with VEGF treatment, indicating the HIF/VEGF system as potentially important in neuron injury response and survival.

Traumatic brain injuries (TBI) are followed by inflammatory response and edema, factors of importance for unfavourable injury outcome. VEGF expression after such injuries was shown to be maximal around 46 days after injury and expressed mainly in astrocytes and inflammatory cells while VEGFR1 and 2 were expressed in blood vessels around the central lesion area from I to 6 days after injury. Thus, the expression of VEGF correlates temporally with the late inflammatory and edema development seen in TBI. Though, VEGFR2 inhibition in TBI did show early increase in the CNS injury markers S100beta and neuron specific enolase (NSE) in serum, increased GFAP positive areas, increased areas devoid of MAP2 and possible increase in TUNEL and FluoroJadeB stainings. This indicates VEGF rather as an endogenous protective factor of importance for favourable injury outcome than as a factor of importance for secondary injuries in TBI.

In summary, these novel findings suggest important roles of both beneficial and possibly detrimental character for VEGF in CNS injury responses.

List of scientific papers

I. Skold M, Cullheim S, Hammarberg H, Piehl F, Suneson A, Lake S, Sjogren A, Walum E, Risling M (2000). Induction of VEGF and VEGF receptors in the spinal cord after mechanical spinal injury and prostaglandin administration. Eur J Neurosci. 12(10): 3675-86.
https://pubmed.ncbi.nlm.nih.gov/11029637

II. Lindholm T, Skold MK, Suneson A, Carlstedt T, Cullheim S, Risling M (2004). Semaphorin and neuropilin expression in motoneurons after intraspinal motoneuron axotomy. Neuroreport. 15(4): 649-54.
https://pubmed.ncbi.nlm.nih.gov/15094469

III. Skold MK, Marti HH, Lindholm T, Linda H, Hammarberg H, Risling M, Cullheim S (2004). Induction of HIF1alpha but not HIF2alpha in motoneurons after ventral funiculus axotomy-implication in neuronal survival strategies. Exp Neurol. 188(1): 20-32.
https://pubmed.ncbi.nlm.nih.gov/15191799

IV. Skold MK, von Gertten V, Sandberg-Nordquist AC, Mathiesen T, Holmin S (2004). VEGF and VEGF receptor expression after experimental brain contusion in rat. [Manuscript]

V. Skold MK, Risling M, Holmin S (2004). Inhibition of VEGF receptor 2 avtivity in TBI results in elevated S100beta and NSE serum levels. [Manuscript]