VEGF in vascular pathology and neurodegeneration

VEGF signaling is essential for normal vascular development and homeostasis. However, under pathological conditions, high levels of VEGF may induce the formation of pathological vessels through angiogenesis. Thus, VEGF signaling is induced after an ischemic stroke or upon CNS injury and may cause cerebral angiogenesis, increased blood-brain barrier permeability, and dysfunction¹.

VEGF is also implicated in neurodegeneration and may play a neuroprotective role in Alzheimer’s disease (AD)². VEGF expression is reduced in AD, which was demonstrated both in the patients' serum in vivo³ and in cerebral capillaries in post-mortem brain tissue⁴. Treating APP transgenic mice with VEGF can reduce memory impairment and beta-amyloid deposition⁵. Furthermore, elevated VEGF levels in cerebrospinal fluid are associated with more optimal human brain aging in vivo. The neuroprotective effect of VEGF appears strongest in AD biomarker–positive individuals, particularly those who are tau positive⁶.

VEGF in cell proliferation and gene expression

The Ras/MAPK pathway regulates cell proliferation and gene expression. The pathway begins with PLCγ after it has been activated by VEGF binding to its receptor, VEGFR2, which participates in all of the vascular epithelial growth factor receptors 1-3 pathways⁷.

PLCγ activates DAG (diacylglycerol), a second-messenger signaling lipid that facilitates the movement of PKC from the cytosol to the plasma membrane⁸. This activates serine proteinase K (SPK), which turns on the Ras protein, a small GTPase responsible for cell proliferation^9,10.

Ras-mediated activation of the serine/threonine protein kinase Raf1 leads to downstream activation of MAP2/ERK kinase (MEK), which in turn phosphorylates ERK1/2. Activated ERK proteins have pleiotropic effects on the cell, including gene expression control in the cell division cycle¹⁰.

VEGF in cytoskeletal rearrangement

VEGF binding to VEGFR stimulates FAK (focal adhesion of kinase) and paxillin. These two proteins are involved in rearranging the cytoskeleton, which occurs by focal adhesion turnover to produce migration¹¹.

Paxillin is a signal-transducing adaptor protein. It is an accessory to the main protein, FAK, in the signal transduction pathway and adheres to the extra-cellular matrix¹².

FAK is a cytosolic protein tyrosine kinase that concentrates on the focal adhesions of cells attached to the extracellular matrix. It affects cell motility by engaging integrins, transmembrane proteins that allow FAK to organize the intracellular cytoskeleton¹³.

VEGF in cell survival and regulation

Src is a non-receptor tyrosine kinase that activates when VEGF binds to its receptor on the cell surface. It promotes angiogenesis and plays a role in regulating embryonic development, cell growth, and cell survival¹⁴.

Src first activates PI3K, an enzyme involved in cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. Activated PI3K phosphorylates the membrane-localized phospholipid PIP3 (phosphatidyl 3,4,5 triphosphate), which activates the downstream signaling component Akt. Akt participates in glucose metabolism, cell proliferation, cell migration, gene transcription, and signaling.

In its role as a regulator of apoptosis, Akt inhibits the action of the Bad (BCL2 associated agonist of cell death)¹⁵ and Caspase-9 (Casp9) proteins. Bad promotes cell death, and by inhibiting it, Akt promotes cell survival. Casp9 is an enzyme that is also pro-apoptotic and is also inhibited by Akt¹⁶.

VEGF in vascular permeability

VEGF enhances microvascular permeability and is sometimes referred to as vascular permeability factor (VPF). VEGF-mediated induction of vascular permeability begins with PLCγ activation.

In addition to participating in the Ras/MAPK signaling pathway to regulate cell proliferation, PLCγ activates PKC through the signaling lipid diacyl glycerol (DAG). One of the functions of PKC is to release intracellular calcium (Ca²⁺), which activates endothelial nitric oxide synthase (eNOS). eNOS catalyzes L-arginine conversion into citrulline and free radical nitric oxide (NO). NO gas diffuses rapidly into blood vessels to increase vascular permeability¹⁷.

Following activation by VEGFR2, PLCγ can also activate the signaling phospholipid inositol triphosphate (IP3). When activated, calcium enters the intracellular space and initiates the same eNOS-mediated vascular permeability cascade described above.

Download our VEGF pathway poster

What to expect

​​VEGF signaling plays a key role in the formation and growth of blood vessels. During the formation of new blood vessels, VEGF is implicated in the induction of gene expression, regulation of vascular permeability, and promotion of cell migration, proliferation, and survival.

VEGF signaling is induced by the binding of VEGF ligands to their cognate membrane-bound receptors, which results in the activation of multiple downstream pathways.

VEGF signaling cascade includes:

• the Ras/MAPK pathway, regulating cell proliferation and gene expression
• the FAK/paxillin pathway, involved in the rearrangement of the cytoskeleton
• the PI3K/AKT pathway, regulating cell survival
• the PLCγ pathway, controlling vascular permeability

For a complete guide to VEGF and angiogenesis products, visit our VEGF portfolio.

References

1. Zhang, Z.G., Zhang, L. & Jiang, Q. VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain.  J. Clin. Invest.  106, 829–838 (2000).

2. Storkebaum, E. & Carmeliet, P. VEGF: a critical player in neurodegeneration.  J. Clin. Invest.  113, 14–18 (2004).

3. Mateo, I.  et al.  Low serum VEGF levels are associated with Alzheimer's disease.  Acta Neurol. Scand.  116, 56–58 (2007).

4. Provias, J. & Jeynes, B. Reduction in vascular endothelial growth factor expression in the superior temporal, hippocampal, and brainstem regions in Alzheimer's disease.  Curr. Neurovasc. Res.  11, 202–209 (2014).

5. Wang, P.  et al.  VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer's disease.  Biochem. Biophys. Res. Commun.  411, 620–626 (2011).

6. Hohman, T.J., Bell, S.P. & Jefferson, A.L. Alzheimer’s Disease Neuroimaging Initiative. The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease.  JAMA Neurol.  72, 520–529 (2015).

7. Shibuya, M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies.  Genes Cancer  2, 1097–1105 (2011).

8. Luo, B., Prescott, S.M. & Topham, M.K. Association of diacylglycerol kinase zeta with protein kinase C alpha: spatial regulation of diacylglycerol signaling.  J. Cell Biol.  160, 929–937 (2003).

9. Bahar, M.E., Kim, H.J. & Kim, D.R. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.  Signal Transduct. Target. Ther.  8, 455 (2023).

10. Avraham, H.K.  et al.  Vascular endothelial growth factor regulates focal adhesion assembly in human brain microvascular endothelial cells through activation of the focal adhesion kinase and related adhesion focal tyrosine kinase.  J. Biol. Chem.  278, 36661–36668 (2003).

11. Hagel, M.  et al.  The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling.  Mol. Cell. Biol.  22, 901–915 (2002).

12. Bachir, A.I., Horwitz, A.R., Nelson, W.J. & Bianchini, J.M. Actin-based adhesion modules mediate cell interactions with the extracellular matrix and neighboring cells.  Cold Spring Harb. Perspect. Biol.  9, a023234 (2017).

13. Chou, M.T., Wang, J. & Fujita, D.J. Src kinase becomes preferentially associated with the VEGFR, KDR/Flk-1, following VEGF stimulation of vascular endothelial cells.  BMC Biochem.  3, 32 (2002).

14. Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins.  Nat. Rev. Mol. Cell Biol.  20, 175–193 (2019).

15. Bates, D.O. Vascular endothelial growth factors and vascular permeability.  Cardiovasc. Res.  87, 262–271 (2010).

16. Jubaidi, F.F.  et al.  The role of PKC–MAPK signalling pathways in the development of hyperglycemia-induced cardiovascular complications.  Int. J. Mol. Sci.  23, 8582 (2022).

17. Sjöberg, E.  et al.  Endothelial VEGFR2–PLCγ signaling regulates vascular permeability and antitumor immunity through eNOS/Src.  J. Clin. Invest.  133, e161366 (2023).