Fig. 2

In a hypoxic environment, hydroxylation and degradation of HIF-1α are inhibited. Therefore, HIF-1α can dimerize, enter the nucleus and transcriptionally regulate the expression of its target genes through the transcription factor HRE. This way it regulates a wide range of pathophysiological processes including angiogenesis. The inflammatory and hypoxic microenvironment in the endometrium regulates the expression of several proteins such as receptors ERBB, NOTCH3 and TGF-β, which trigger a cascade of signalling pathways (JAK/STAT, SMAD and PI3K/AKT/mTOR) finally leading to increase in gene expression VEGF, PDGF, Bcl-XL, MMP9, Ang-2 and Tie-2. The result is culmination in proangiogenic transcriptional responses including proliferation and migration, and inhibition of apoptosis. Increased expression of Ang-2 which competitively binds Tie-2, inhibits Ang-1/Tie-2 signaling and negates its stabilizing effects. The destabilizing effect of Ang-2 on blood vessels and the proliferative and migratory effects of VEGF lead to vascular growth and angiogenesis. [eNOS = endothelial nitric oxide synthase, ERK = extracellular signal-regulated kinase, MAPK = mitogen-activated protein kinase, PDGF = platelet-derived growth factor, PGF = placental growth factor, PI3K = phosphatidylinositol-3-kinase, HRE = hypoxia responsive element, GRB7 = Human Growth Factor Receptor Bound Protein 7, NOTCH3 = Human Neurogenic Locus Notch Homolog Protein 3, PGR = Human progesterone receptor, MIEN1 = Migration And Invasion Enhancer 1, ERBB = the human epidermal growth factor receptor, JAK = Janus kinases, STAT = signal transducer and activator of transcription proteins, MMP9 = matrix metallopeptidase 9, CASP = cysteine-aspartic proteases, P4 = progesteron]