Abstract
Background/AimThe 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.MethodsWild-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.ResultsAng 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 saline-treated 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.ConclusionThe results of the present indicate that Ang II can directly regulate the proliferation and migration of LECs through AT1R in vivo and in vitro, which may provide new potential treatments for Ang II-induced hypertension and cardiac remodeling.
Highlights
The lymphatic system comprises lymphatic capillaries, precollecting vessels and collecting vessels, all of which are composed of a single layer of lymphatic endothelial cells (LECs) (Hu et al, 2019)
We evaluated the effect of Angiotensin II (Ang II) on lymphangiogenesis in the mouse hearts and the gene expression profiles in cultured primary mouse LECs using time-series microarrays and attempted to elucidate the possible mechanism by which Ang II regulates LEC proliferation and migration, which are crucial for lymphangiogenesis
Ang II infusion significantly upregulated the mRNA expression levels of both lymphatic vessel hyaluronan receptor-1 (LYVE-1) and VEGFR-3, markers of lymphangiogenesis, in the heart tissues compared with that observed in the sham control, whereas this increase was fully inhibited by losartan administration (Figures 1B,C)
Summary
The lymphatic system comprises lymphatic capillaries, precollecting vessels and collecting vessels, all of which are composed of a single layer of lymphatic endothelial cells (LECs) (Hu et al, 2019). Several LEC markers, such as lymphatic vessel hyaluronan receptor-1 (LYVE-1), Prox, Foxc, CCL21, and vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3) are all highly expressed in most lymphatic vessels during development. Lymphatic capillaries continue to express high levels of LYVE-1, Prox, VEGFR-3, and low level of Podoplanin (Yang et al, 2012). It is important to elucidate the regulatory mechanisms underlying lymphatic vessel growth ( known as lymphangiogenesis)
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