Angiogenesis in obesity and cancer

Angiogenesis is the process of blood vessel growth from pre-existing vasculatures. In the adult, it is involved in certain physiological processes, such as in organ and tissue regeneration, wound healing, and in female reproductive cycles. Like during embryonic development, the growth and expansion of adult tissues is dependent on neovascularization.

The adipose tissue has a unique capacity to substantially increase or decrease in size throughout adult life. This indicates that blood vessels in adipose tissues must be tightly regulated to grow or to regress depending on nutritional state. Active angiogenesis also occurs under many pathological conditions, including diabetic retinopathy, psoriasis, rheumatoid arthritis, cancer and metastasis.

The aims of this thesis are to elucidate the reciprocal regulation of angiogenesis and adipose tissue expansion and obesity, and to determine the antiobesity and antitumor activity of novel or established angiogenesis inhibitors in animal models. We found that leptin induced neovascularization, and synergistically stimulated angiogenesis with FGF-2 and VEGF. Thus leptin may modulate VEGF- or FGF-2-stimulated neovascularization in tissues, such as the adipose tissue, that co-express these factors. Interestingly, leptin, similar to VEGF, induced endothelial fenestrations and vascular leakage.

Leptin may play an important role in the maintenance of a fenestrated vascular bed in adipose tissues. A switch of an angiogenic phenotype in most, if not all, tissues usually requires both up-regulation of angiogenesis stimulators and down-regulation of inhibitors. In our efforts to identify adipocyte-derived angiogenesis inhibitors, we found that adiponectin selectively inhibited endothelial cell growth and angiogenesis in two rigorous in vivo angiogenesis models. In a tumor model, adiponectin was found to suppress tumor growth and neovascularization. The anti-endothelial mechanisms of adiponectin involved induction of endothelial cell apoptosis by cascade activation of endothelial caspases-8, -9 and 3. This finding provides the first example that the adipose tissue produces angiogenesis inhibitors. Because the levels of adiponectin in the circulation are relatively high in healthy individuals, decreased production of adiponectin in obese individuals may be correlated with increased risks of angiogenesis-dependent disorders, such as cancer.

To develop novel therapies against obesity, we examined the effect of TNP-470, a well-characterized angiogenesis inhibitor, in animal obesity models, including high-fat diet fed wt mice and genetically obese, ob/ob mice. We found that TNP-470 remarkably prevented both genetic and diet-induced obesity in mice. The anti-obesity effect was associated with a decreased vascularity of the adipose tissue. Our data indicate that adipose tissue growth is angiogenesis-dependent, and that the angiogenesis inhibitor TNP-470 prevented obesity irrespective of aetiology. To identify novel oral angiogenesis inhibitors that potentially can be used in prevention and treatment of angiogenesis-dependent disorders, we investigated polyphenols present in natural food products. Our laboratory was the first to report that green tea epigallocathecin-3-gallate (EGCG) was an oral angiogenesis inhibitor.

In this thesis work, we studied the effects of resveratrol, a natural polyphenol present in grapes and red wine. We found that resveratrol directly inhibited endothelial cell growth via suppression of the MAPK pathway. In vivo, resveratrol was found to be a potent oral angiogenesis inhibitor, affecting both physiological and pathological angiogenesis-dependent processes, such as wound healing and tumor growth. The potential anti-obesity effects of resveratrol remain to be studied.

List of scientific papers

I. Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y (2001). Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A. 98(11): 6390-5. Epub 2001 May 08
https://pubmed.ncbi.nlm.nih.gov/11344271

II. Brakenhielm E, Cao R, Angelin B, Parini P, Cao Y (2003). Angiogenesis inhibitor, TNP-470, prevents both diet-induced and genetic obesity in mice. [Manuscript]

III. Brakenhielm E, Veitonmaki N, Cao R, Zhivotovsky B, Funahashi T, Cao Y (2003). Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial apoptosis. [Manuscript]

IV. Brakenhielm E, Cao R, Cao Y (2001). Suppression of angiogenesis, tumor growth, and wound healing by resveratrol, a natural compound in red wine and grapes. FASEB J. 15(10): 1798-800.
https://pubmed.ncbi.nlm.nih.gov/11481234