Angiotensin converting enzyme 2 (ACE2) is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) receptor pathway. Here, we report that higher ACE2 expression correlates with better overall survival in patients with clear cell renal cell carcinoma (ccRCC). Moreover, ACE2 has inhibitory effects on tumor proliferation in ccRCC in vitro and in preclinical animal models of ccRCC. We further show that Ang-(1-7), a heptapeptide generated by ACE2, is the likely mediator of this effect. Vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI) treatment of ccRCC xenografts decreased ACE2 expression, and combination treatment with VEGFR-TKI and Ang-(1-7) generated additive suppression of tumor growth and improved survival outcomes. Last, the addition of Ang-(1-7) to programmed death-ligand 1 (PD-L1) pathway inhibitor and VEGFR-TKI showed further growth suppression in an immunocompetent RCC model. Together, these results suggest that targeting the ACE2/Ang-(1-7) axis is a promising therapeutic strategy against ccRCC.
Background
Angiotensin converting enzyme 2 converts angiotensin (Ang) II into the biologically active heptapeptide Ang‐(1‐7). We have previously shown that Ang‐(1‐7) is involved in the stimulation and homeostasis of circulating endothelial progenitor cells, and that Ang‐(1‐7) is an endogenous ligand for the G protein‐coupled receptors Mas and MrgD. To better understand the role of the peptide in endothelial cell biology and homeostasis and the receptors involved, we aimed to investigate the effect of Ang‐(1‐7) on various functional parameters of endothelial cells.
Methods and Results
Ang‐(1‐7) was just as effective as vascular endothelial growth factor (VEGF) at stimulating endothelial tube formation in an in‐vitro Matrigel based assay in HUVEC. To investigate the effects in a more physiological model, we isolated aortas from Mas, MrgD, and Mas/MrgD deficient animals together with age and gender matched controls in an ex‐vivo model of sprouting. While aortas with a deficiency in either Mas or MrgD still showed normal number and length of sprouts as wild type mice, aortic rings deficient for Mas/MrgD showed a reduction in sprout length by 87% and no of sprouts by 77% when compared with wild type controls. We were also able to show that Mas deficient mice had a reduction in circulating CD34+ cells, a marker for heamopoeitic stem cells. Finally, we were able to show that after shunting blood flow to the hind limb of mice in an in‐vivo hind limb ischemia assay, Ang‐(1‐7) was able to restore 62.2% of blood flow in comparison with 17.1% in solvent‐treated mice.
Conclusion
All together, our data suggest a key role for Ang‐(1‐7) and its receptors in sprouting angiogenesis, vascular homeostasis, and thus might be a promising new option for the treatment of peripheral vascular disease.
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