The Role that VEGF and the VEGFR play in Glioblastoma Angiogenesis

Figure 1: Function of VEGF Overview (Qiagen Company, 2013)

Angiogenesis begins when tumor cells release proangiogenic factors (Bao et al, 2006) such as the vascular endothelial growth factor (VEGF) (Black et al, 2005). VEGF is one of the most potent factors playing a role in the formation of angiogenesis (Choudhury et al, 2010).

 VEGF functions by diffusing into nearby tissues and binding to receptors on the endothelial cells of the preexisting blood vessels, activating them (Black et al, 2005). The interaction between VEGF and the endothelial cells stimulates proliferation, migration, survival, and increases blood vessel leakiness as well as plasma protein extravasation (Choudhury et al, 2010). VEGF also plays a role in the production of nitric oxide (NO) by stimulation of endothelial nitric oxide synthase further activating the angiogenic cascade (Cooke et al, 2013) and stimulating the migration of monocytes and neutrophil (Choudhury et al, 2010).

There are six VEGF homologues that have been identified (Cho et al, 2003). VEGF-A is the major promoter of angiogenesis because of it’s high potency and specific responses to endothelial cells (Nagy et al, 2007). The expression of VEGF-A is facilitated by hypoxia-inducible factor 1 (HIF-1) and a transcriptional regulator (containing α and β subunits) (Choudhury et al, 2010). 

The presence of VEGF is dependent upon the binding of HIF-1 (Harada et al, 2007). In hypoxic conditions, HIF-1 binds increasing the transcription of VEGF-A, therefore increasing VEGF-A protein secretion (Choudhury et al, 2010). In turn the expression of VEGF-1 is increased, which results in angiogenesis (Bussolati et al, 2006). In hypoxic conditions, TSP-1 is down regulated, which is unfortunate because TSP-1 inhibits endothelial cell division and tube formation (Taraboletti et al, 2010).

Figure 2: Hypoxia Condition Overview (Case Western Reserve University, 2013)

In ischemia, a condition where the glucose and oxygen intake is depleted, (Fraum et al, 2011) intracellular signaling via the MAPK pathway increases resulting in endothelial cell proliferation (Seger et al, 1995).

     

Figure 3: Activation of PKB/AKT and its targets (Scheid et al, 2001)

The MAPK pathway functions through VEGF-A (Doanes et al, 1999). This pathway begins with the phosphorylation of PI3K, activating Pkb/Akt, (Hemmings et al, 2012) inducing endothelial cell survival (Shiojima et al, 2002). VEGFR-2 complexes are also activated reducing p53, p21, and BAX expression, resulting in an increase of BCL-2 expression (Brakenhielm, 2007) promoting further survival in endothelial cells (Choudhury et al, 2010).  

When the expression of VEGFR-1 and VEGFR-2 is increased, tumor angiogenesis is initiated (Vrendenburgh et al, 2007) via integrin interactions with VEGFR-2 (Choudhury et al, 2010).  Both VEGFR-1 and VEGFR-2 are important receptors involved in signaling with VEGF-A (Olsson et al, 2006). VEGF-A, released by tumors, signals to VEGFR-1 for support of the vascular system (Roskoski, 2007).

The microenvironment is also involved in angiogenesis because of VEGFR-1 expression. Not only is VEGFR-1 expressed on endothelial cells, but also, macrophages, pericytes, vascular smooth endothelial muscle, progenitor cells, EPC’s (bone marrow endothelial cells), and hematopoietic cells (Hall, 2006).

Involving the microenvironment strengthens angiogenesis because VEGFR-1 is the receptor for the placental P1GF (placental growth factor), VEGF-A, (Carmeliet et al, 2001) and VEGF-B (Hoeben et al, 2013). Upon the binding of VEGF-B tumor progression and metastasis is promoted via proteolytic enzymes (Bambace et al, 2011).

VEGFR-3, a receptor for VEGF-C and VEGF-D, (Lawrence et al, 2003) is also up regulated. Because it is a key regulator of angiogenesis, binding to VEGFR-3 promotes angiogenesis and metastasis in the lymphatic system (Choudhury et al, 2005).

             Figure 4: VEGFR system overview (Universita Degli Studi di Brescia a, 2013)

To summarize, VEGFR-1 is in charge of drawing other cells to the system (Nam et al, 2004), VEGFR-2 is essential for endothelial cell contribution to angiogenesis (Black et al, 2006), and VEGFR-2 aids in the metastasis of the lymphatic system (Choudhury et al, 2010).