Blockade of VEGFR2 and Not VEGFR1 Can Limit Diet-Induced Fat Tissue Expansion: Role of Local versus Bone Marrow-Derived Endothelial Cells

Abstract

BackgroundWe investigated if new vessel formation in fat involves the contribution of local tissue-derived endothelial cells (i.e., angiogenesis) or bone marrow-derived cells (BMDCs, i.e. vasculogenesis) and if antiangiogenic treatment by blockade of vascular endothelial growth factor (VEGF) receptors can prevent diet-induced obesity (DIO).Methodology/Principal FindingsWe performed restorative bone marrow transplantation into wild-type mice using transgenic mice expressing green fluorescent protein (GFP) constitutively (driven by β-actin promoter) or selectively in endothelial cells (under Tie2 promoter activation) as donors. The presence of donor BMDCs in recipient mice was investigated in fat tissue vessels after DIO using in vivo and ex vivo fluorescence microscopy. We investigated the roles of VEGF receptors 1 and 2 (VEGFR1/VEGFR2) by inducing DIO in mice and treating them with blocking monoclonal antibodies. We found only marginal (less than 1%) incorporation of BMDCs in fat vessels during DIO. When angiogenesis was inhibited by blocking VEGFR2 in mice with DIO, treated mice had significantly lower body weights than control animals. In contrast, blocking VEGFR1 had no discernable effect on the weight gain during DIO.Conclusions/SignificanceFormation of new vessels in fat tissues during DIO is largely due to angiogenesis rather than de novo vasculogenesis. Antiangiogenic treatment by blockade of VEGFR2 but not VEGFR1 may limit adipose tissue expansion.

Adipose tissue remodeling and obesity

“…In brief, VEGF functions by binding two tyrosine kinase receptors, VEGF-R1 and VEGF-R2; the latter is expressed in vascular endothelial cells, and signaling through this receptor is critical for both physiological and pathological blood vessel formation. Blockade of VEGF-R2, but not VEGF-R1, restricts AT expansion and thus prevents the progression of DIO (81). Remarkably, blockade through use of a VEGF-R2 antibody can further inhibit preadipocyte differentiation (82).…”

Angiogenesis and development of adipose tissue

“…A recent study showed that blockade of VEGFR-2 but not VEGFR-1, using monoclonal antibodies, can limit diet-induced fat tissue expansion in mice. The results also indicated that angiogenesis from local preexisting vasculature, and not the contribution of bone marrow-derived cells, primarily sustains new vessel formation in fat tissue during diet-induced obesity (Tam et al, 2009). Another strategy to reduce fat mass via its vasculature may be to target prohibitin, a multifunctional membrane protein selectively expressed in adipose tissue endothelial cells (Kolonin et al, 2004).…”

Effect of vascular endothelial growth factor receptor 2 antagonism on adiposity in obese mice

“…The similar distribution of white blood cells suggests that the rat antibody DC101 and the mouse antibody 1C8 did not elicit a markedly different immune response. In a previous study, treatment of C57Bl/6 mice with DC101 (40 mg/kg every 3 days) had no effect on body weight during the first 5-6 weeks of HFD feeding, but afterwards (weeks 6-13), the rate of weight gain decreased significantly compared with the HFD controls (Tam et al 2009). This was associated with a significantly decreased food intake in the DC101 group that was apparently not observed in the first 5-6 weeks.…”

“…A previous study has revealed expression of different isoforms of VEGF-A, VEGF-B, and VEGF-C and the receptors VEGF-R1, VEGF-R2, and VEGF-R3 in subcutaneous (SC) and gonadal (GON) adipose tissues of mice (Voros et al 2005). Furthermore, blockade of VEGF-R2 but not VEGF-R1 in mice was shown to limit diet-induced fat tissue expansion and suggested a role in early phase fat tissue development (Tam et al 2009). In addition, several studies have suggested a link between the VEGF/VEGF-R2 pathway and insulin sensitivity and glucose tolerance (Elias et al 2012, Wada et al 2010.…”