Abstract
Studies have demonstrated that nuclear factor of activated T cells 5 (NFAT5) is not only a tonicity‐responsive transcription factor but also activated by other stimuli, so we aim to investigate whether NFAT5 participates in collateral arteries formation in rats. We performed femoral artery ligature (FAL) in rats for hindlimb ischaemia model and found that NFAT5 was up‐regulated in rat adductors with FAL compared with sham group. Knockdown of NFAT5 with locally injection of adenovirus‐mediated NFAT5‐shRNA in rats significantly inhibited hindlimb blood perfusion recovery and arteriogenesis. Moreover, NFAT5 knockdown decreased macrophages infiltration and monocyte chemotactic protein‐1 (MCP‐1) expression in rats adductors. In vitro, with interleukin‐1β (IL‐1β) stimulation and loss‐of‐function studies, we demonstrated that NFAT5 knockdown inhibits MCP‐1 expression in endothelial cells and chemotaxis of THP‐1 cells regulated by ERK1/2 pathway. More importantly, exogenous MCP‐1 delivery could recover hindlimb blood perfusion, promote arteriogenesis and macrophages infiltration in rats after FAL, which were depressed by NFAT5 knockdown. Besides, NFAT5 knockdown also inhibited angiogenesis in gastrocnemius muscles in rats. Our results indicate that NFAT5 is a critical regulator of arteriogenesis and angiogenesis via MCP‐1‐dependent monocyte recruitment, suggesting that NFAT5 may represent an alternative therapeutic target for ischaemic diseases.
Highlights
Interventional therapy and bypass surgery are effective treatments for patients with coronary heart disease (CHD), these procedures are not suitable for some patients and are associated with a high postoperative restenosis rate.[1,2] Well-developed coronary collateral circulation (CCC) is crucial for improving the symptoms and prognosis of CHD patients.[3,4] investigating the regulatory mechanism of CCC formation and promoting the opening and development of CCC to reconstruct a patient's autologous blood supply may be a promising solution to those patients.Arteriogenesis, the basic process of CCC formation, during which pre-existing small arterioles are remodelled into large and functional collateral arteries to divert blood flow around stenotic lesions, is a complex set of events involving interactions among various cell types and signalling circuits.[5,6] Inflammation plays a crucial role in arteriogenesis.[7]
The primary findings of the present study are as follows: (a) genetical silence of nuclear factor of activated T cells 5 (NFAT5) attenuates arteriogenesis and angiogenesis in rat hindlimb ischaemia model; (b) NFAT5 can regulate monocyte recruitment by regulating the expression of monocyte chemoattractant protein 1 (MCP-1) in endothelial cells (ECs) both in vivo and in vitro; (c) MCP-1 supplementation can reverse the inhibitory effect of NFAT5 knockdown on monocyte recruitment and arteriogenesis
These findings mainly suggest that NFAT5 promotes arteriogenesis via MCP-1-dependent monocyte recruitment
Summary
Interventional therapy and bypass surgery are effective treatments for patients with coronary heart disease (CHD), these procedures are not suitable for some patients and are associated with a high postoperative restenosis rate.[1,2] Well-developed coronary collateral circulation (CCC) is crucial for improving the symptoms and prognosis of CHD patients.[3,4] investigating the regulatory mechanism of CCC formation and promoting the opening and development of CCC to reconstruct a patient's autologous blood supply may be a promising solution to those patients. In human kidney, the high interstitial sodium concentration in the medulla generates a defence zone with enhanced antibacterial immunity via NFAT5/MCP-1-dependent monocytes chemotaxis, mononuclear phagocytes bactericidal activity and cytokine production.[20]. It is not clear whether MCP-1 release and monocytes recruitment during arteriogenesis are determined by NFAT5. We will demonstrate that NFAT5 controls MCP-1 release in ECs, as well as promotes monocytes recruitment and arteriogenesis in hindlimb ischaemia after femoral artery ligation (FAL), in order to discover a new mechanism and provide a novel therapeutic target for the development of collateral circulation
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