On the other hand, depletion of VEGF-A in the pancreatic ��-cells by genetic means essentially eliminates tumor progression beyond the angiogenic stage [21]. The diversity of outcomes nearly in functional studies of VEGF family members is further highlighted by the fact that neutralization of PlGF or blockade of VEGFR-1 in RIP1-Tag2 mice does not affect tumor angiogenesis or growth [26], [36]. To understand the mechanism behind the observed outcomes, the VEGFR-1 and VEGFR-2 occupancy by all different VEGF ligands in the context of ligand over-expression or deficiency have to be considered. In the present study, the transgenically expressed VEGF-B in RIP1-Tag2 islets possibly displaced VEGF-A and PlGF from VEGFR-1, thus diminishing signaling by overtly pro-angiogenic factors.

Conversely, the absence of VEGF-B in RIP1-Tag2; Vegfb?/? mice may enhance the specific signaling by VEGF-A and PlGF through VEGFR-1 in endothelial cells. Moreover, members of the VEGF family have been reported to form heterodimers, the abundance and activity of which is presently still unknown [37], [38], [39]. Additional complexity comes from possible effects on the competitive binding equilibrium of the VEGF family co-receptors neuropilin-1 and -2 [40], which also act as an integral part of the semaphorin and plexin family of angiogenesis regulators [41]. Clearly, more in-depth studies of VEGFR ligand and receptor/co-receptor occupancy following various pharmacological and/or genetic perturbations of the VEGF system are warranted together with functional studies aimed at revealing ligand-specific signaling effectors downstream of VEGFR-1.

A number of possible explanations for the observed effects of VEGF-B on tumor growth relating to cell metabolism or energy usage are discussed below. Firstly, VEGF-B was recently attributed a role in metabolism by controlling the trans-capillary transport of long-chain fatty acids through transcriptional regulation of FATPs in the endothelium [10], [30]. Thus, the release of VEGF-B would allow tissues with a high metabolic turnover, including tumors, to meet their demand for fuel. In the context of pancreatic ��-cell biology, excess lipid exposure is known to be detrimental for both ��-cell function and survival [42]. Moreover, free fatty acids induce the production of the vasodilator nitric oxide in pancreatic islets [43].

Interestingly, indications of diminished lipotoxicity in tumors from RIP1-Tag2; Vegfb?/? mice come from the observations of a decreased rate of ��-cell apoptosis and a constricted vasculature. However, we did not observe increased ��-cell apoptosis Brefeldin_A or tumoral lipid accumulation and fatty acid transporter protein expression in RIP1-Tag2; RIP1-VEGFB tumors. Thus, it is unlikely that the observed changes in tumor growth rate result solely from changes in lipid accumulation and toxicity.