Abstract
Despite the important role that the growth hormone (GH)/IGF-I axis plays in vascular homeostasis, these kind of growth factors barely appear in articles addressing the neovascularization process. Currently, the vascular endothelium is considered as an authentic gland of internal secretion due to the wide variety of released factors and functions with local effects, including the paracrine/autocrine production of GH or IGF-I, for which the endothelium has specific receptors. In this comprehensive review, the evidence involving these proangiogenic hormones in arteriogenesis dealing with the arterial occlusion and making of them a potential therapy is described. All the elements that trigger the local and systemic production of GH/IGF-I, as well as their possible roles both in physiological and pathological conditions are analyzed. All of the evidence is combined with important data from the GHAS trial, in which GH or a placebo were administrated to patients suffering from critical limb ischemia with no option for revascularization. We postulate that GH, alone or in combination, should be considered as a promising therapeutic agent for helping in the approach of ischemic disease.
Highlights
The fact that growth hormone (GH) is a necessary actor for many physiological processes and a real breakthrough for the treatment of many pathological situations beyond simple human longitudinal growth does not need justification [1]
Receptors for GH (GHR) and IGF-I (IGF-IR) are expressed in the vascular endothelium [7,8,9], and some studies have suggested that GH itself is expressed in this special gland of internal secretion [10,11]
In the GHAS trial, we found a parallel and significant increase of VEFG-R2 or KDR/Flk-1 mRNA levels in (VEGFA)-R2 or KDR/flk-1 mRNA levels from muscle samples in the GH group compared to the placebo group (Figure 6A), which confirmed the action of VEGFA, a finding consistent to that from animal models of hindlimb ischemia treated with the IGF-I plasmid [133]
Summary
The fact that growth hormone (GH) is a necessary actor for many physiological processes and a real breakthrough for the treatment of many pathological situations beyond simple human longitudinal growth does not need justification [1]. Receptors for GH (GHR) and IGF-I (IGF-IR) are expressed in the vascular endothelium [7,8,9], and some studies have suggested that GH itself is expressed in this special gland of internal secretion [10,11] These data indicate that GH and IGF-I have to play a very important role in the maintenance of normal endothelial function. Endothelial dysfunction in GHD has been demonstrated by an impaired flow-mediated dilation, which improved with GH treatment [12], indicating that GH played a role in vascular reactivity [13], as had been shown by the group of Napoli [14]. We review here how GH and its mediator IGF-I can act in the arterial wall to favor normal physiological functioning, as well as how both molecules play an important role in collateral remodeling after arterial occlusion. We present some molecular data obtained from the GHAS trial about the benefit of using GH as a rescue therapy in real patients with critical limb ischemia without options for conventional revascularization
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