This review describes the positive effects of growth hormone (GH) on the cardiovascular system. We analyze why the vascular endothelium is a real internal secretion gland, whose inflammation is the first step for developing atherosclerosis, as well as the mechanisms by which GH acts on vessels improving oxidative stress imbalance and endothelial dysfunction. We also report how GH acts on coronary arterial disease and heart failure, and on peripheral arterial disease, inducing a neovascularization process that finally increases flow in ischemic tissues. We include some preliminary data from a trial in which GH or placebo is given to elderly people suffering from critical limb ischemia, showing some of the benefits of the hormone on plasma markers of inflammation, and the safety of GH administration during short periods of time, even in diabetic patients. We also analyze how Klotho is strongly related to GH, inducing, after being released from the damaged vascular endothelium, the pituitary secretion of GH, most likely to repair the injury in the ischemic tissues. We also show how GH can help during wound healing by increasing the blood flow and some neurotrophic and growth factors. In summary, we postulate that short-term GH administration could be useful to treat cardiovascular diseases.

Although not yet well-understood, today it is clear that Growth Hormone (GH) exerts a relevant role in the regulation of ovulation and fertility; in fact, fertility is lower in women with GH deficiency (GHD), and GH receptors (GHR) and GH mRNA have been found in the ovary since the onset of follicular development in humans. However, despite the strong evidence of GH in the regulation of fertility, many aspects of GH actions at this level are still not well-established, and it is likely that some controversial data depend on the species analyzed, the dose of the hormone and the duration of use of GH. Folliculogenesis, ovulation, and corpus luteum formation and maintenance are processes that are critically dependent on angiogenesis. In the ovary, new blood vessel formation facilitates oxygen, nutrients, and hormone substrate delivery, and also secures transfer of different hormones to targeted cells. Some growth factors and hormones overlap their actions in order to control the angiogenic process for fertility. However, we still know very little about the factors that play a critical role in the vascular changes that occur during folliculogenesis or luteal regression. To promote and maintain the production of VEGF-A in granulosa cells, the effects of local factors such as IGF-I and steroids are needed; that VEGF-A-inducing effect cannot be induced by luteinizing hormone (LH) or chorionic gonadotropin (CG) alone. As a result of the influences that GH exerts on the hypothalamic-pituitary-gonadal axis, facilitating the release of gonadotropins, and given the relationship between GH and local ovarian factors such as VEGF-A, FGF-2, IGF-1, or production of sex steroids, we assume that GH has to be a necessary factor in ovarian angiogenesis, as it happens in other vascular beds. In this review we will discuss the actions of GH in the ovary, most of them likely due to the local production of the hormone and its mediators.

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.

This review describes the positive effects of growth hormone on the cardiovascular 13 system. We analyze why the vascular endothelium is a real internal secretion gland, whose 14 inflammation is the first step for developing atherosclerosis, as well as the mechanisms by which 15GH acts on the vascular endothelium improving its dysfunction. We also report how GH acts on 16 coronary arterial disease and heart failure, and on peripheral arterial disease inducing the 17 generation of new collateral vessels able to bypass a major artery occlusion. We include some 18 preliminary data from a trial in which GH or placebo is given to elder people suffering from critical 21We also analyze how Klotho may have strong relationships with GH, inducing, after being released 22 from the damaged vascular endothelium, the pituitary secretion of GH to repair the damaged tissue. 23Lastly, we show how GH induces wound healing by increasing the blood flow to the ischemic tissue. 24In summary, we postulate that short-time GH administration is useful for treating cardiovascular 25 diseases. 26

Revascularization for chronic limb-threatening ischemia (CLTI) is necessary to alleviate symptoms and wound healing. When it fails or is not possible, there are few alternatives to avoid limb amputation in these patients. Although experimental studies with stem cells and growth factors have shown promise, clinical trials have demonstrated inconsistent results because CLTI patients generally need arteriogenesis rather than angiogenesis. Moreover, in addition to the perfusion of the limb, there is the need to improve the neuropathic response for wound healing, especially in diabetic patients. Growth hormone (GH) is a pleiotropic hormone capable of boosting the aforementioned processes and adds special benefits for the redox balance. This hormone has the potential to mitigate symptoms in ischemic patients with no other options and improves the cardiovascular complications associated with the disease. Here, we discuss the pros and cons of using GH in such patients, focus on its effects on peripheral arteries, and analyze the possible benefits of treating CLTI with this hormone.

Wound healing is complex and numerous factors overlap perfectly with the goal of wound closure. Among them, we will focus on a large amount of experimental and clinical evidence on the action of GH in wound repair. We will analyze how the physiological rhythm of GH secretion influences this process, and also one of the most important signaling pathways that mediate the effects of GH on tissue regeneration. The role of IGF-1 and the factors that stimulate GH secretion and that have also been shown to improve healing will also be reviewed. In addition, it will be analyzed the cellular senescence process, which plays a key role in nonhealing wounds associated with chronic diseases. The benefit of GH in this last circumstance is especially important. The lesions associated with catabolic states, mainly burns, are considered a delicate situation in which it is extraordinarily difficult to act with growth factors due to the fragile situation of these patients, often children. The positive action of GH in these states will also be described. In summary, we will analyze many evidences about the beneficial effects of GH and its main secretagogues in the healing of wounds.

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Despite the important role that the 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 has turned to be considered as an authentic gland of internal secretion due to the wide variety of released factors and functions with local effect, including the paracrine/autocrine production of GH or IGF-I, for which the endothelium has specific receptors. In this comprehensive review, it will be described the evidence involving these proangiogenic hormones in arteriogenesis dealing with the arterial occlusion and making of them a potential therapy. It will be analyzed all those elements triggering the local and systemic production of GH/IGF-I and their possible role both in physiological and pathological conditions. The whole evidence will be combined with important data from the GHAS trial, in which GH or 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 the ischemic disease.A normal embryonic development needs the formation of blood vessels [21]; after birth there is also the need of the formation of new blood vessels while growing, but also in some physiological processes such as the menstrual cycle in women and the development of the mammary gland during pregnancy [22], but apart from these situations, adult neovascularization rarely takes place and when it happens it is associated with pathological affectations, such as wounds, muscle injuries, fractures or hypoxia/ischemia. The question now would be: how does neovascularization occur in adults and what is the role of the GH / IGF-I system in it?As it seems logical, hypoxia is a very important stimulus for the growth of new blood vessels [23], triggering this growth through hypoxia-inducible factors (HIF) that act on the expression of proangiogenic factors, but also that of anti-angiogenic factors to achieve the perfect number and size of the vessels necessary to compensate for the lack of oxygen supply and to regenerate the tissue [23]. This is a clear and well-established fact for angiogenesis. However, when a progressive narrowing of the vascular lumen appears, preexisting collaterals will have to growth to compensate the lack of distal flow which is triggered in a totally different way. With independence of that, the stimulation of endothelial nitric oxide synthase (eNOS) that leads to the production of nitric oxide (NO) from the vascular endothelium seems to be the key mediator for both kind of reparative processes. NO is a potent vasodilator, therefore increasing blood supply to the zone affected by hypoxia/ischemia. This implies changes in the vascular tone, vasorelaxation and vasopermeability, which are affected in arteries suffering an atherosclerotic damage. Interestingly, GH activates the NO pathway [14,24] throughout direct mechanisms tha...