Angiotensin AT ₁ and AT ₂ Receptors Differentially Regulate Angiopoietin-2 and Vascular Endothelial Growth Factor Expression and Angiogenesis by Modulating Heparin Binding–Epidermal Growth Factor (EGF)–Mediated EGF Receptor Transactivation

Abstract

Angiotensin II (Ang II)-mediated signals are transmitted via heparin binding epidermal growth factor (EGF)-like growth factor (HB-EGF) release followed by transactivation of EGF receptor (EGFR). Although Ang II and HB-EGF induce angiogenesis, their link to the angiopoietin (Ang)-Tie2 system remains undefined. We tested the effects of Ang II on Ang1, Ang2, or Tie2 expression in cardiac microvascular endothelial cells expressing the Ang II receptors AT(1) and AT(2). Ang II significantly induced Ang2 mRNA accumulations without affecting Ang1 or Tie2 expression, which was inhibited by protein kinase C inhibitors and by intracellular Ca(2+) chelating agents. Ang II transactivated EGFR via AT(1), and inhibition of EGFR abolished the induction of Ang2. Ang II caused processing of pro-HB-EGF in a metalloproteinase-dependent manner to stimulate maturation and release of HB-EGF. Neutralizing anti-HB-EGF antibody blocked EGFR phosphorylation by Ang II. Ang II also upregulated vascular endothelial growth factor (VEGF) expression in an HB-EGF/EGFR-dependent manner. AT(2) inhibited AT(1)-mediated Ang2 expression and phosphorylation of EGFR. In an in vivo corneal assay, AT(1) induced angiogenesis in an HB-EGF-dependent manner and enhanced the angiogenic activity of VEGF. Although neither Ang2 nor Ang1 alone induced angiogenesis, soluble Tie2-Fc that binds to angiopoietins attenuated AT(1)-mediated angiogenesis. These findings suggested that (1) Ang II induces Ang2 and VEGF expression without affecting Ang1 or Tie2 and (2) AT(1) stimulates processing of pro-HB-EGF by metalloproteinases, and the released HB-EGF transactivates EGFR to induce angiogenesis via the combined effect of Ang2 and VEGF, whereas AT(2) attenuates them by blocking EGFR phosphorylation. Thus, Ang II is involved in the VEGF-Ang-Tie2 system via HB-EGF-mediated EGFR transactivation, and this link should be considerable in pathological conditions in which collateral blood flow is required.

Retinal Angiogenesis Is Mediated by an Interaction between the Angiotensin Type 2 Receptor, VEGF, and Angiopoietin

“…These findings together with a reduction in Ang2 mRNA following AT2-RB indicate an interaction between the retinal RAS and Ang2-Tie2 systems in promoting retinal angiogenesis. Previous studies in BRECs 30 and cultured cardiac cells 31 are in agreement with an interaction between the RAS and angiopoietins, with AT1-RB reducing Ang2 mRNA. Whether ANG II modulates the gene expression of Tie2 in retinal cells is not known, however in cultured cardiac endothelial cells, ANG II was reported to have no effect on Tie2 mRNA.…”

“…Whether ANG II modulates the gene expression of Tie2 in retinal cells is not known, however in cultured cardiac endothelial cells, ANG II was reported to have no effect on Tie2 mRNA. 31 Similarly, in the present study, AT2-RB did not influence the gene expression of Tie2.…”

“…29 There are limited studies which have examined the relationship between the RAS, VEGF/VEGF-R2, and angiopoietin-Tie2 systems in blood vessel growth. 30,31 Furthermore, to our knowledge the interaction between the AT2 receptor and VEGF/VEGF-R2 and angiopoietin-Tie2 in an in vivo model of retinal angiogenesis is unknown. In the present study we aimed firstly to determine whether AT2 receptor blockade (AT2-RB) would attenuate retinal angiogenesis in a rat model of ROP, and secondly whether this was associated with alterations in VEGF/ VEGF-R2 and angiopoietin-Tie2 gene expression.…”

Angiotensin II Angiogenic Effect In Vivo Involves Vascular Endothelial Growth Factor- and Inflammation-Related Pathways

“…First, Ang II may influence the angiogenic reaction by increasing vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) synthesis, two key growth factors implied in the angiogenic process (Cross and Claesson-Welsh, 2001). Hence, Ang II increases VEGF expression in endothelial cells and in an in vivo corneal assay (Fujiyama et al, 2001;Otani et al, 1998). The angiogenic response to VEGF might involve the production of nitric oxide (NO), as previously described in ischemia-induced angiogenesis (Murohara et al, 1998).…”

Estudo comparativo entre tratamento convencional e tratamento com heparina tópica para a analgesia de queimaduras

“…The anti-inflammatory action results from deactivation of pro-inflammatory cytokines such as TNF-alpha 10 , selectins secreted by leukocytes such as CD11b 11,12 integrins such as ICAM-1 13 and attenuation of complement activation 14 . Angiogenic effect derives from the interaction with vascular endothelium growth factor (VEGF) 15,16 and with fibroblasts' growth factors (FGFs) 17,18 .…”