STAT3 potentiates the ability of airway smooth muscle cells to promote angiogenesis by regulating VEGF signalling

Abstract

What is the central question of this study? Airway angiogenesis occurs in asthma, and airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis. What is the potential mechanism by which ASM cells harvested from patients with asthma are capable of promoting airway angiogenesis? What is the main finding and its importance? Endogenous STAT3 mediated the pro-angiogenic ability of ASM cells by directly activating VEGF signalling. These findings contribute to the understanding of airway angiogenesis in pathology and could represent a possible therapeutic target for asthma. Airway angiogenesis indicates the specific vascular structure remodelling that occurs in asthma. Airway smooth muscle (ASM) cells have been reported to be capable of promoting airway angiogenesis; however, the potential mechanism is not yet fully defined. Herein, we investigated the role of signal transducer and activator of transcription 3 (STAT3) in the progress of airway angiogenesis. Western blot analysis showed that STAT3 activation was aberrantly upregulated in ASM tissues of patients with asthma and ASM cells that were exposed to cytokines to imitate the airway conditions in patients with asthma. Compared with the control group, both the inhibition of STAT3 activation and the silencing of endogenous STAT3 in ASM cells significantly reduced the proliferation, migration and tube-forming ability of human lung microvascular endothelial cells induced by the conditioned medium (CM) of ASM cells. The increased proliferation and migration of human aortic vascular smooth muscle cells were also repressed by inhibition of STAT3 in ASM cells. Besides, the increased activity of VEGF signalling was observed in ASM cells and the CM by RT-PCR and Western blotting assay, whereas this increased activity was reduced by STAT3 silencing. Further studies indicated that STAT3 regulated VEGF activation by directly interacting with the binding site on the 5' region of the VEGF gene. The increase in STAT3-induced pro-angiogenic activity of ASM cells was significantly decreased by administration of VEGF neutralizing antibody. In conclusion, we provided evidence that endogenous STAT3 mediates the pro-angiogenic ability of ASM cells by directly activating VEGF signalling, which could represent a possible therapeutic target for asthma.

Astaxanthin inhibits homocysteine‑induced endothelial cell dysfunction via the regulation of the reactive oxygen species‑dependent VEGF‑VEGFR2‑FAK signaling pathway

“…The VEGF-VEGFR2 axis aids endothelial cell recruitment and vascular permeability, whereas ERK activates endothelial cell proliferation; FAK promotes cell migration and invasion. VEGF and VEGFR2 have been considered to be the most important factors in this pathway, and serve key roles in regulating angiogenesis via the modulation of the degradation, differentiation, proliferation and migration of vascular endothelial cells (36–40). The VEGF-VEGFR axis eventually promotes the formation of new blood vessels (36–39).…”

MicroRNA-590-5p represses proliferation of human fetal airway smooth muscle cells by targeting signal transducer and activator of transcription 3

“…Furthermore, knockdown of STAT3 inhibits PDGF-induced ASM cell proliferation through the down-regulation of cyclin D3 and up-regulation of p27 expression [ 21 ]. A recent study reported that STAT3 promotes the pro-angiogenesis ability of ASM cells through up-regulation of vascular endothelial growth factor [ 37 ]. These studies suggest that STAT3 is a promising molecular target in preventing ASM cell proliferation.…”

Suppression of autophagy through JAK2/STAT3 contributes to the therapeutic action of rhynchophylline on asthma

“…Activation of STAT3 is found in peripheral blood mononuclear cells and airway smooth muscle tissues from asthma patients [9] and correlated with the increased cytokines [10]. Inhibition of STAT3 signaling can remit the airway inflammation [11], inhibit the proliferation of airway smooth muscle cells (ASMCs) and angiogenesis [9], and regulate IgE produce [12]. However, whether STAT3 signaling pathway could mediate the function of rhynchophylline on asthma remains unclear.…”