Modulation of Angiogenesis during Adipose Tissue Development in Murine Models of Obesity

Abstract

Development of vasculature and mRNA expression of 17 pro- or antiangiogenic factors were studied during adipose tissue development in nutritionally induced or genetically determined murine obesity models. Subcutaneous (SC) and gonadal (GON) fat pads were harvested from male C57Bl/6 mice kept on standard chow [standard fat diet (SFD)] or on high-fat diet for 0-15 wk and from male ob/ob mice kept on SFD. Ob/ob mice and C57Bl/6 mice on high-fat diet had significantly larger SC and GON fat pads, accompanied by significantly higher blood content, increased total blood vessel volume, and higher number of proliferating cells. mRNA and protein levels of angiopoietin (Ang)-1 were down-regulated, whereas those of thrombospondin-1 were up-regulated in developing adipose tissue in both obesity models. Ang-1 mRNA levels correlated negatively with adipose tissue weight in the early phase of nutritionally induced obesity as well as in genetically determined obesity. Placental growth factor and Ang-2 expression were increased in SC adipose tissue of ob/ob mice, and thrombospondin-2 was increased in both their SC and GON fat pads. mRNA levels of vascular endothelial growth factor (VEGF)-A isoforms VEGF-B, VEGF-C, VEGF receptor-1, -2, and -3, and neuropilin-1 were not markedly modulated by obesity. This modulation of angiogenic factors during development of adipose tissue supports their important functional role in obesity.

Angiogenesis and development of adipose tissue

“…PlGF and Ang-2 expression were increased in SC adipose tissue of ob/ob mice and TSP-2 was increased in both their SC and GON fat pads. mRNA levels of VEGF-A isoforms, VEGF-B, VEGF-C, VEGFR-1, -2 and -3 and Np-1 were not markedly modulated by obesity (Voros et al, 2005). Several angiogenic factors, like VEGF-C, VEGF-D, sVEGFr2 angiopoietin-2, angiogenin and the angiogenesis inhibitor endostatin are significantly elevated in either overweight or obese subjects compared to lean controls.…”

“…TIE-1, TIE-2, VEGFR-2 and VEGFR-3 are not expressed at detectable levels (Voros et al, 2005). Development of vasculature and mRNA expression of pro-or anti-angiogenic factors were also studied during adipose tissue development in nutritionally induced (HFD) or genetically determined (ob/ob) murine obesity models (Voros et al, 2005). Ob/ob mice and C57Bl/6 mice on HFD had significantly larger subcutaneous (SC) and gonadal (GON) fat pads, accompanied by significantly higher blood content, increased total blood A c c e p t e d M a n u s c r i p t vessel volume and higher number of proliferating endothelial cells, as compared to lean controls.…”

“…Loss of PlGF impairs angiogenesis in the ischemic retina, limb, and heart, in wounded skin and in tumors, without affecting physiological angiogenesis (Carmeliet et al, 2001). PlGF is expressed in murine adipose tissue, both in adipocytes and in the stromal-vascular cell fraction (Voros et al, 2005).…”

“…VEGF-B, VEGF-C and VEGFR-1 mRNA levels are less modulated during differentiation. TIE-1, TIE-2, VEGFR-2 and VEGFR-3 are not expressed at detectable levels (Voros et al, 2005). Development of vasculature and mRNA expression of pro-or anti-angiogenic factors were also studied during adipose tissue development in nutritionally induced (HFD) or genetically determined (ob/ob) murine obesity models (Voros et al, 2005).…”

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations

“…Both receptors bind ligands that are known to promote angiogenesis during excessive WAT development in different strains of mice fed a high-fat diet ( 26,27 ). The VEGF receptor-2 (KDR) gene, encoding an early marker of endothelial cell differentiation, was also decreased ( 28 ).…”