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Activation of the AT1R/HIF-1 α /ACE axis mediates angiotensin II-induced VEGF synthesis in mesenchymal stem cells.

Liu C, Zhang JW, Hu L, Song YC, Zhou L, Fan Y, Zhu HY, Wang Y, Li QP - Biomed Res Int (2014)

Bottom Line: We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R).The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II.We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

View Article: PubMed Central - PubMed

Affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.

ABSTRACT
A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

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Scheme of Ang II-driven VEGF synthesis. Ang II induction sensing via HIF-1α or STAT3 activates an autocrine loop of ACE upregulation, Ang II formation, and signaling via AT1R, which exerts a positive feedback and further fosters VEGF synthesis in MSCs.
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fig5: Scheme of Ang II-driven VEGF synthesis. Ang II induction sensing via HIF-1α or STAT3 activates an autocrine loop of ACE upregulation, Ang II formation, and signaling via AT1R, which exerts a positive feedback and further fosters VEGF synthesis in MSCs.

Mentions: We have reported previously that Ang II stimulation could increase VEGF synthesis in MSCs through the ERK1/2 and Akt pathways via the AT1R [6]. This study examined the pathway that regulates ACE following activation of the AT1R by Ang II. Here, we report for the first time that ACE is upregulated after Ang II stimulation, and ACE upregulation also increases VEGF synthesis in MSCs (Figure 1). The upregulation of ACE appeared after the rapid degradation of exogenous Ang II and led to the formation of endogenous Ang II (Figure 4). Endogenous Ang II would be expected to continue to exert biological effects. We suggest that exogenous Ang II, as a trigger, induces VEGF synthesis with the formation of an Ang II-AT1R-ACE-VEGF autocrine system (Figure 5). In this process, exogenous Ang II is rapidly degraded. Neprilysin, an endopeptidase expressed on the cell surface, is the main enzyme responsible for degrading Ang II in preadipocytes and adipocytes [21]. Given the high activity of neprilysin in MSCs [22, 23], we attribute the rapid degradation of exogenous Ang II to neprilysin. A local RAS in MSCs was discovered 10 years ago [1]. The RAS components, angiotensinogen, renin, ACE, and AT receptors, were found to be present in cultured MSCs. The de novo synthesis of Ang II by MSCs was also detected. These findings demonstrated that a potential autocrine-paracrine mechanism existed in the local RAS of MSCs [1]. In this study, we also revealed that ACE activity of MSCs was raised by Ang II stimulation (Figure 1). Ang II concentration in culture media of MSCs increased from 4 h to 21 h (Figure 4), which was a result of the balance between ACE and neprilysin activities. In summary, a transient high level of exogenous Ang II acts as a trigger to upregulate ACE and induces a positive feedback of the RAS in MSCs. Although Schunkert et al. [24] reported Ang II infusion decreased ACE mRNA levels in the lung and testis of rats, later studies have confirmed a positive feedback effect on the local RAS with an ACE/AT1R-dependent mechanism in the kidney [25, 26].


Activation of the AT1R/HIF-1 α /ACE axis mediates angiotensin II-induced VEGF synthesis in mesenchymal stem cells.

Liu C, Zhang JW, Hu L, Song YC, Zhou L, Fan Y, Zhu HY, Wang Y, Li QP - Biomed Res Int (2014)

Scheme of Ang II-driven VEGF synthesis. Ang II induction sensing via HIF-1α or STAT3 activates an autocrine loop of ACE upregulation, Ang II formation, and signaling via AT1R, which exerts a positive feedback and further fosters VEGF synthesis in MSCs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221905&req=5

fig5: Scheme of Ang II-driven VEGF synthesis. Ang II induction sensing via HIF-1α or STAT3 activates an autocrine loop of ACE upregulation, Ang II formation, and signaling via AT1R, which exerts a positive feedback and further fosters VEGF synthesis in MSCs.
Mentions: We have reported previously that Ang II stimulation could increase VEGF synthesis in MSCs through the ERK1/2 and Akt pathways via the AT1R [6]. This study examined the pathway that regulates ACE following activation of the AT1R by Ang II. Here, we report for the first time that ACE is upregulated after Ang II stimulation, and ACE upregulation also increases VEGF synthesis in MSCs (Figure 1). The upregulation of ACE appeared after the rapid degradation of exogenous Ang II and led to the formation of endogenous Ang II (Figure 4). Endogenous Ang II would be expected to continue to exert biological effects. We suggest that exogenous Ang II, as a trigger, induces VEGF synthesis with the formation of an Ang II-AT1R-ACE-VEGF autocrine system (Figure 5). In this process, exogenous Ang II is rapidly degraded. Neprilysin, an endopeptidase expressed on the cell surface, is the main enzyme responsible for degrading Ang II in preadipocytes and adipocytes [21]. Given the high activity of neprilysin in MSCs [22, 23], we attribute the rapid degradation of exogenous Ang II to neprilysin. A local RAS in MSCs was discovered 10 years ago [1]. The RAS components, angiotensinogen, renin, ACE, and AT receptors, were found to be present in cultured MSCs. The de novo synthesis of Ang II by MSCs was also detected. These findings demonstrated that a potential autocrine-paracrine mechanism existed in the local RAS of MSCs [1]. In this study, we also revealed that ACE activity of MSCs was raised by Ang II stimulation (Figure 1). Ang II concentration in culture media of MSCs increased from 4 h to 21 h (Figure 4), which was a result of the balance between ACE and neprilysin activities. In summary, a transient high level of exogenous Ang II acts as a trigger to upregulate ACE and induces a positive feedback of the RAS in MSCs. Although Schunkert et al. [24] reported Ang II infusion decreased ACE mRNA levels in the lung and testis of rats, later studies have confirmed a positive feedback effect on the local RAS with an ACE/AT1R-dependent mechanism in the kidney [25, 26].

Bottom Line: We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R).The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II.We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

View Article: PubMed Central - PubMed

Affiliation: Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, China.

ABSTRACT
A local renin-angiotensin system (RAS) is expressed in mesenchymal stem cells (MSCs) and regulates stem cell function. The local RAS influences the survival and tissue repairing ability of transplanted stem cells. We have previously reported that angiotensin II (Ang II) pretreatment can significantly increase vascular endothelial growth factor (VEGF) synthesis in MSCs through the ERK1/2 and Akt pathways via the Ang II receptor type 1 (AT1R). However, the role of angiotensin-converting enzyme (ACE) has not been clarified. Furthermore, whether Ang II pretreatment activates hypoxia-inducible factor-1α (HIF-1α) in MSCs has not been elucidated. Our data show that both ACE and HIF-1α are involved in promoting VEGF expression in MSCs, and that both are upregulated by Ang II stimulation. The upregulation of ACE appeared after the rapid degradation of exogenous Ang II, and led to the formation of endogenous Ang II. On the other hand, the ACE inhibitor, captopril, attenuated Ang II-enhanced HIF-1α upregulation, while HIF-1α suppression markedly attenuated ACE expression. This interesting finding suggests an interaction between ACE and HIF-1α. We conclude that Ang II pretreatment, as a trigger, activated the AT1R/HIF-1α/ACE axis that then mediated Ang II-induced VEGF synthesis in MSCs.

Show MeSH
Related in: MedlinePlus