Figure 1.

Effects of growth hormone (GH) on the vascular endothelium. The interaction GH–GHR (growth hormone receptor) produces the activation of the associated Janus kinase 2 (JAK2), which induces the phosphorylation (red circles) of tyrosine located in the cytoplasmic receptor domain, leading to the phosphorylation of GH-signaling pathways, such as signal transducers and activators of transcription (STATS). Among STATS (STATS 1 and 3 not shown in the Figure), STAT5 homodimerizes and is translocated to the nucleus, where it induces the transcription of a series of genes. Activated JAK2, acting on the insulin receptor substrate (IRS) induces the phosphorylation of phosphoinositide 3-kinase (PI3K) which, in turn, activates the cell survival factor serine-threonine kinase (Akt). This inhibits the proapoptotic enzyme Caspase 3 (red arrow), but it also activates endothelial nitric oxide synthase (eNOS) (blue arrow). Activated eNOS promotes the synthesis of nitric oxide (NO) (from L-Arginine and O2) and the formation of L-Citrulline. The formed NO flows from the cytoplasm to the muscle cell layer of the blood vessels, producing its relaxation and consequent vasodilation. The interaction GH–GHR also induces the activation of the Shc adapter proteins, which leads to the activation of the Grb2–SOS–Ras–Raf–MEK–ERK (extracellular signal-regulated kinase) pathway (Raf is not shown in the figure). Activated ERK translocates into the nucleus of the endothelial cells (ECs) and regulates the expression of genes involved in cell proliferation, differentiation, and survival, but it also regulates cell motility and migration (key for the formation of new vessels). The GH–GHR interaction also activates focal adhesion kinase (FAK). SHP: protein tyrosine phosphatase. Blue arrows: stimulation. Red arrow: inhibition. Black arrows: Translocation to the nucleus. 1: endocrine GH. 2: endothelial GH: plays and auto/paracrine role and in situations of the absence of endocrine GH perhaps plays the role of the former (black line).