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J Am Coll Cardiol, 2005; 46:835-837, doi:10.1016/j.jacc.2005.06.008
(Published online 9 August 2005). © 2005 by the American College of Cardiology Foundation |
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Angiogenesis Research Center, Section of Cardiology, Departments of Medicine and Pharmacology and Toxicology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
* Reprint requests and correspondence: Dr. Michael Simons, Section of Cardiology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, New Hampshire 03756 (Email: michael.simons{at}dartmouth.edu).
On the cardiovascular side, diabetes has long been associated with accelerated atherosclerosis (1). More recently, a number of abnormalities associated with disregulation of neovascularization have also been recognized. These include abnormally enhanced angiogenesis, defined as capillary vessel growth (2), in the retina, leading to diabetic retinopathy (3) and in the vessel wall, potentially producing atherosclerotic plaque destabilization (4). At the same time, insufficient angiogenesis has been implicated in abnormal wound healing, leading to diabetic skin ulcers (5). Defective arteriogenesis, a process of formation or remodeling of arterioles and arteries (2), has also been reported in diabetic patients (6–8). Impaired release of endothelial progenitor cells from the bone marrow (9) and defective function of these cells (10) are other features of diabetes that further contribute to abnormal neovascularization and increased cardiovascular risk.
The molecular defects underlying these angiogenic abnormalities have generated much interest but, so far, have remained elusive. Diabetic patients have been reported to have a reduced number of circulating endothelial progenitor cells, with the extent of reduction directly proportional to plasma hemoglobin A1c levels (9). There are also reports of reduced vascular endothelial growth factor (VEGF) and VEGF receptors expression in the myocardium of diabetic patients (11) as well as increased production of an angiogenesis inhibitor angiostatin induced by hyperglycemia (7).
This set of observations presents a confusing picture that seems to defy a common molecular mechanism. An important study in this issue of the Journal might lay the groundwork for unraveling this puzzle. Sasso et al. (12) have examined the expression and function of VEGF and its receptors in patients with advanced coronary disease undergoing coronary artery bypass surgery. In an admittedly somewhat small sample of twenty patients, they demonstrated increased VEGF expression in the myocardium of diabetic patients compared with non-diabetic patients, whereas expression levels of VEGF receptors 1 and 2 (Flt-1 and Flk-1, respectively) were reduced. Most importantly, the extent of Flk-1 phosphorylation, a reflection of its activation status, was severely reduced in diabetic patients compared with non-diabetic patients. This was associated with a reduced activation of serine-threonine protein kinase Akt-1 and endothelial nitric oxide synthase (eNOS), the principal effectors of the VEGF signaling pathway.
These results extend previous observations of abnormal VEGF signaling in diabetic patients first reported by Waltenberger et al. (13), who noted that monocytes from diabetic patients failed to respond to VEGF in a cell migration assay despite activation of the Flt-1 receptor. Taken together, these two studies suggest that whereas Flt-1 activation under diabetic conditions is normal, Flk-1 activation is not. The role of Flt-1 in VEGF signaling remains controversial. Unlike Flk-1, which is expressed almost exclusively in the endothelium and in certain bone marrow cell populations, including endothelial precursor cells, Flt-1, in addition to the endothelium, it is expressed in a wide range of mononuclear cells, including monocytes. It seems to be involved in the regulation of cell migration either via an independent signaling pathway or secondary to Flk-1 activation via an intracellular cross-talk or direct receptor heterodimerization.
Flk-1 is currently thought to be the principal receptor involved in transmitting VEGF signaling (Fig. 1). It regulates cell proliferation via activation of the extracellular receptor kinase (Erk-1/2) and Akt-1, a master regulator of cell function. Among many Akt-1 activities, two are the most crucial in this context: activation of eNOS, thereby stimulating nitric oxide production, a step required for endothelial cell proliferation, and inhibition of apoptosis. The latter VEGF/Akt-1 activity is probably necessary for the maintenance of the intact vasculature in adult tissues.
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With a disease as complex as diabetes, other factors are likely to be involved as well. Thus, the presence of advanced glycation end-products might well play an important role in suppressing arteriogenesis (15). For example, glycation of circulating growth factors such as fibroblast growth factor (FGF) has been shown to markedly reduce its biological activity, which, in turn, can inhibit VEGF-dependent signaling (16). It is also possible that intracellular signaling defects in diabetes are not limited to VEGF, but include other important arteriogenic growth factors such as FGFs, platelet-derived growth factors, hepatocyte growth factor, and placenta growth factor.
Clearly, much research remains to be done, although these discoveries have immediate clinical implications, particularly with regard to ongoing trials of therapeutic angiogenesis (2,17). If defective arteriogenesis in diabetic patients is, indeed, secondary to a VEGF signaling defect, therapeutic efforts should be directed not at futile attempts to further increase tissue or plasma VEGF levels, but at restoration of intracellular signaling, a strategy that will likely require small molecule agents.
In summary, the study by Sasso et al. (12) provides yet another important piece in a puzzle that is the arteriogenic defects of diabetes. The emergence of the VEGF (and perhaps other growth factors) defective signaling paradigm in diabetes promises to enhance our understanding of cardiovascular complications of diabetes and to redirect therapeutic efforts to search for intracellular drug targets.
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