The hypothesis of a detrimental role for IGF-1 and other growth factors in the development of vascular disease (1) has not been consistently supported by recent studies (2,3). New evidence suggests that cellular senescence (4) and impaired vascular endothelial proliferation, adhesion, and incorporation play a pivotal role in the development of macrovascular disease (5). Indeed, recent data on large numbers suggest that higher IGF-1 bioavailability may protect against the onset of ischemic heart disease (6,7) and glucose intolerance (8) and, in type 2 diabetic patients, may offer improved metabolic control and prevent vascular complications (9,10). Other potential beneficial actions of IGF-1 in cardiovascular physiology include increased nitric oxide synthesis and K+ channel opening (11,12), and this may explain the impaired small-vessel function associated with low IGF-1 levels in patients with cardiovascular syndrome X (12). By counteracting oxidized LDL-induced cytotoxicity and vascular smooth muscle cell apoptosis, IGF-1 may protect against plaque instability and rupture (2). In patients with acute myocardial infarction, markedly reduced IGF-1 values are associated with a worse outcome (13,14), and recent data suggest that intramyocardial (15,16) or vascular (17) gene delivery of growth factors can improve symptoms and exercise capacity in patients with coronary or peripheral vascular disease.
We were therefore surprised by two recent studies proposing IGF-1 as a mediator of harmful vascular effects (18,19). The authors found an inverse association between IGF binding protein (IGFBP)-1 and carotid intimal-medial thickness (r = −0.135, P = 0.041) (18), macrovascular disease (19), and hypertension (19) in patients with type 2 diabetes. IGFBP-1 is a minor component of the system of IGFBPs 1–6, first discovered in the 1990s, and regulated by a complex group of proteases and phosphatases (20). As IGFBP-1 is generally assumed to inhibit IGF-1 bioavailability (21), the authors conclude that IGF-1 exerted harmful vascular effect (18,19).
We propose two different interpretations of the above data, not necessarily exclusive. First, the reduced IGFBP-1 concentration observed in situations of vascular disease (18,19) could result from activation of a compensatory mechanism leading to higher IGF-1 bioavailability. This interpretation is confirmed by the finding in hypertensive patients of higher IGF-1 levels than in control subjects (22), and of a positive association among IGF-1, insulin sensitivity, and preserved vasodilator capacity (23,24). Indeed, in these patients, IGF-1 was the main independent predictor of both coronary reserve and insulin sensitivity (23). Second, alternatively or additionally, one should consider that the interaction between IGF-1 and its binding proteins is complex. An adequate serum amount of total IGFBP-1 is essential for IGF-1’s biological activity (8,25), independently of its phosphorilation status. Moreover, overexpression of IGFBP-1 attenuates IGF-1’s growth-promoting actions in vitro but enhances them in vivo (26). Thus, a threshold concentration of IGFBP-1 might enhance, rather than impair, IGF-1’s bioactivity through a partial agonism-like action.
Because IGFBPs have been characterized only recently and their physiology in humans is not completely understood, we think further studies are needed to better understand the true value of the IGF-1/IGFBP axis in promoting or protecting against vascular complications.
References
Address correspondence to Elena Conti, MD, Institute of Cardiology, Catholic University, Via Todi 60, 00181 Rome. E-mail: [email protected].
