Vascular endothelial growth factor and diabetes - The agonist versus antagonist paradox

Much of the morbidity and mortality associated with diabetes is primarily a ttributable to sequelae of microvascular and macrovascular disease. Over th e past decade, dramatic progress has been achieved in elucidating the funda mental processes underlying the pathogenesis of these complications. Angiog enic factors in particular now appear to play a pivotal role in the develop ment of microvascular complications as well as the response to macrovascula r disease. Hyperglycemia, other growth factors, advanced glycation end prod ucts, oxidative stress, and ischemia can increase growth factor expression. In some microvascular tissues, the result is pathologic neovascularization and increased vascular permeability. These responses account for much of t he visual loss associated with diabetic retinopathy and may, in addition, s erve a significant role in nephropathy and neuropathy. In contrast, recent data suggest that vascular collateralization resulting from ischemia-induce d growth factor release in tissues compromised by macrovascular disease may be important in reducing clinical symptoms and tissue damage. This angioge nic response, which may be beneficial in coronary artery and peripheral lim b disease, appears to be reduced in patients with diabetes. Thus, two appar ently diametrically opposed therapeutic paradigms are arising for the treat ment of vascular complications in diabetes. Indeed, growth factor antagonis ts have been used successfully in diabetes-related animal models to block a ngiogenic and permeability complications in the retina and kidney. Converse ly, growth factor agonists have been successfully used to stimulate collate ral vessel formation and reduce ischemic symptoms from macrovascular diseas e in the coronary arteries and peripheral limbs. Both of these approaches a re currently being evaluated in clinical trials for their respective indica tions. Thus, as these divergent therapeutic modalities begin to enter the c linical arena, this apparent paradox necessitates careful consideration of the potential risks, benefits, and interactions of the opposing regimens. U sing vascular endothelial growth factor as a classic example of growth fact or involvement, we discuss the current preclinical and clinical data suppor ting these approaches and the implications arising from the probable coexis tence of these two therapeutic modalities.