Chronic limb-threatening ischemia could benefit from growth hormone therapy for wound healing and limb salvage

Abstract

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.

Keywords: angiogenesis; arteriogenesis; chronic limb-threatening ischemia; growth hormone; neuropathic response; redox balance; wound healing.

Figure 1.

Computed tomography angiogram (CTA) showing the leg flow of a patient with chronic limb-threatening ischemia. Note the diffuse disease and heavy calcification (green arrows) of the arteries with several and long occlusions (red arrow) affecting the femoropopliteal and distal vessels.

Figure 2.

Vascular adaptation following an ischemic insult. It has been divided into two different periods: short and long term. Observe both kinds of compensation process: microcirculatory and collateral. A-v, arteriovenous; NO, nitric oxide.

Figure 3.

(a) GH effects on the cardiovascular system at the heart and peripheral level. (b) (1) GH effects can be mediated by the activation of its own receptor (GHR) or that of PRL (PRLR). (2) Factors involved in the response to GH. BDNF, brain-derived neurotrophic factor; EGF, epidermal growth factor; eNOS, endothelial NO synthase; EPO, erythropoietin; FGF, fibroblast growth factor; GH, growth hormone; GHR, growth hormone receptor; IGF-1, insulin-like growth factor 1; NO, nitric oxide; PRL, prolactin; PRLR, prolactin receptor; SDF-1/CXCL12, stromal cell-derived factor 1/C-X-C motif chemokine 12; VEGF, vascular endothelial growth factor.

Figure 4.

Arteriogenesis. The increased shear stress forces produced by an arterial occlusion trigger the NO pathway activation, which in last term is the factor responsible for the onset of new functional collaterals. NO production inhibits VE-cadherin expression, which physiologically plays a pivotal role for maintaining the integrity of the vascular membrane, therefore allowing increased vascular permeability and monocytes and macrophages entry into the vascular wall. Blue arrows indicate stimulation and red arrows inhibition. NO, nitric oxide; VE, vascular-endothelial.

Figure 5.

Summary of GH actions for neovascularization and wound healing at different levels. At the BM level the hormone enhances the production and release of EPCs which peripherally mature to ECs. On ECs the hormone activates eNOS leading to NO production; this contributes to improve redox balance. GH decreases peripheral resistances by decreasing SNS. The hormone also acts on the IS leading to an increase in T and B-lymphocytes and the production of antibodies. GH exerts actions on the neurogenic response that results in an increase in SP production. These effects may lead to: (A) angiogenesis, as a result of hypoxia there is a sprout of new capillaries; (B) arteriogenesis, the occlusion of an artery (a) increases shear stress forces that act on preexisting collateral arterioles (b, c) enlarging them and allowing blood flow to bypass the occlusion (b1, c1). Wound healing is one of the consequences of the recovery of blood flow. BM, bone marrow; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; GH, growth hormone; IS, immune system; NO, nitric oxide; ROS, reactive oxygen species; SNS, sympathetic nervous system; NS, peripheral nervous system;SP, Substance P. SP, Substance P.

Figure 6.

Typical neuropathic wound with torpid evolution in a diabetic patient that previously underwent endovascular revascularization. Note the hyperkeratotic edge of the wound and the lack of healing.

Figure 7.

Evolution of a neuropathic wound in a tetraplegic patient treated with topic GH administration (0.5 mg/day). GH, growth hormone.

Figure 8.

Neurogenic response. Schematic design of the mechanisms involved in the inflammation process triggered by neuropathy. It represents the connection between nervous and immune system that contributes to the wound healing. SP and neurotrophins are the mediator molecules. +, stimulation; -, inhibition; IL-1, interleukin-1; NK-cells, natural killer-cells; SP, Substance P.

Figure 9.

Hematoxylin-eosin stained histological section of an ischemic muscle. (a) Note the fat infiltration with numerous vacuoles. (b) Extensive inflammatory infiltration, centralization of nuclei and interfiber edema. (c) Immunohistochemistry showing CD31 cells; note the small number of stained capillaries. Magnification 40×.

Figure 10.

Intracellular mechanisms by which GH produces angiogenesis or arteriogenesis or may be inactivated. (1) After the interaction between GH and its receptor (GHR) a cascade of signaling pathways is initiated by JAK2 activation leading to the expression of a number of genes. (2) The GHR may be internalized together with GH and translocated to the nucleus where it may also activate gene expression. (3) GH and GHR may suffer a lysosomal degradation after being internalized, but also, depending on the tissue, the hormone may suffer a specific proteolytic cleavage giving origin to vasoinhibins (4) which may block both angiogenesis and arteriogenesis. This represents a mechanism of control for both processes. (5) Among the genes expressed SOCS acts by inhibiting GH signaling, directly or affecting the translocation of the GHR to the nucleus of the cell. (6, 7) Cells may express GH that acts in an autocrine (6) or paracrine (7) manner. This cellular production of the hormone may lead to an interaction with the membrane GHR (8) impeding the effects of endocrine or exogenously administered hormone, or even may produce the desensitization of GHR. On the left of the figure, signals responsible for angiogenesis (upper) and arteriogenesis (lower) can be seen. Blue arrows, stimulation; red arrows and squares, inhibition. +, activation; -, inhibition; Akt, serin threonine kinase; DLL4-Notch-VEGF axis, Delta like 4-Notch-vascular endothelial growth factor axis; GH, growth hormone; GHR, growth hormone receptor; JAK/STATs, Janus kinase/signal transducer and activator of transcription; NO, nitric oxide; RAS-ERK, rats sarcoma-extracellular signal-regulated kinases; Rho, hexameric protein found in prokaryotes, necessary for the process of terminating the transcription of some genes; SOCs, suppressor of cytokine signaling.