Angiotensin II Stimulates the Proliferation and Migration of Lymphatic Endothelial Cells Through Angiotensin Type 1 Receptors

Abstract

Background/Aim: The proliferation and migration of lymphatic endothelial cells (LECs) is essential for lymphatic vessel growth (also known as lymphangiogenesis), which plays a crucial role in regulating the tissue fluid balance and immune cell trafficking under physiological and pathological conditions. Several growth factors, such as VEGF-C, can stimulate lymphangiogenesis. However, the effects of angiotensin II (Ang II) on the proliferation and migration of mouse LECs and the underlying potential mechanisms remain unknown. Methods: Wild-type mice were infused with Ang II (1,000 ng/kg/min) for 1-2 weeks. Murine LECs were stimulated with Ang II (500 nM) or saline for 12-48 h. Cell proliferation was determined with 5-bromo-2-deoxyuridine (BrdU) incorporation assays, while cell migration was assessed by scratch wound healing and transwell chamber assays. The gene expression profiles were obtained by time series microarray and real-time PCR analyses. Results: Ang II treatment significantly induced lymphangiogenesis in the hearts of mice and the proliferation and migration of cultured LECs in a time-dependent manner. This effect was completely blocked by losartan, an angiotensin II type 1 receptor (AT1R) antagonist. The microarray results identified 1,385 differentially expressed genes (DEGs) at one or more time points in the Ang II-treated cells compared with the control salinetreated cells. These DEGs were primarily involved in biological processes and pathways, including sensory perception of smell, the G protein coupled receptor signaling pathway, cell adhesion, olfactory transduction, Jak-STAT, alcoholism, RIG-I-like receptor and ECM-receptor interaction. Furthermore, these DEGs were classified into 16 clusters, 7 of which (Nos. 13, 2, 8, 15, 7, 3, and 12, containing 586 genes) were statistically significant. Importantly, the Ang II-induced alterations the expression of lymphangiogenesis-related genes were reversed by losartan.

VEGF‐C/VEGFR‐3 axis protects against pressure‐overload induced cardiac dysfunction through regulation of lymphangiogenesis

“…However, the present results indicated that LECs are the main cell type expressing VEGF‐C and VEGFR‐3. Although our recent data demonstrate that angiotensin II markedly increases VEGFR‐3 expression and lymphangiogenesis in mouse LECs though the angiotensin type I receptor, 30 the precise mechanisms by which pressure overload regulates VEGF‐C or VEGFR‐3 expression in LECs remain unclear. A previous study has shown that Tbx1, a member of the T‐box family of transcription factors, can upregulate VEGFR‐3 expression in endothelial cells by binding to an enhancer element within the Vegfr‐3 gene 31 .…”

Autoantibodies Targeting AT1- and ETA-Receptors Link Endothelial Proliferation and Coagulation via Ets-1 Transcription Factor

“…In addition, in contrast to SRC-IgG, neither AT-II nor ET-1 increased HMEC-1 proliferation. AT-II has, however, recently been associated with increased proliferation in lymphatic endothelial cells, and previously in human umbilical vein endothelial cells (HUVECs) [ 20 , 51 ]. AT 1 R stimulation triggered angiogenesis in both instances, a mechanism not involved in the present work.…”

Sirtuin 3 deficiency aggravates angiotensin II‐induced hypertensive cardiac injury by the impairment of lymphangiogenesis

“…Furthermore, we observed a positive effect of SIRT3 on VEGFC‐VEGFR3, where this growth factor is found includes myocardial cells, fibroblasts and macrophages, but the specific mechanism of action of SIRT3 upregulating VEGFC has yet to be elucidated. In addition, it was reported that low‐dose, short‐time administration of Ang II induced compensatory lymphangiogenesis in heart 34 . However, lymphangiogenic function was decreased in decompensatory stage of hypertensive cardiac remodelling with inflammation, fibrosis and heart failure 5 .…”

“…In addition, it was reported that low‐dose, short‐time administration of Ang II induced compensatory lymphangiogenesis in heart. 34 However, lymphangiogenic function was decreased in decompensatory stage of hypertensive cardiac remodelling with inflammation, fibrosis and heart failure. 5 Our study validated the latter.…”