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Hypertensive Stimuli Indirectly Stimulate Lymphangiogenesis through Immune Cell Secreted Factors

ABSTRACT: (1) Background: Renal immune cells and lymphatic vessel (LV) density have been reported previously to be increased in multiple mouse models of hypertension (HTN). However, whether interstitial levels of HTN stimuli such as angiotensin II, salt, or asymmetric dimethylarginine have a direct or indirect effect on lymphangiogenesis is unknown. We hypothesized that these 3 HTN stimuli directly increase lymphatic endothelial cell (LEC) proliferation, LEC 3-D matrix invasion and vessel formation, and sprouting of mouse mesometrial LVs. (2) Methods: Human LECs (hLECs) and mouse LECs (mLECs) were treated with HTN stimuli while explanted mouse mesometrial LVs were treated with either the same HTN stimuli or with HTN stimuli-conditioned media. Conditioned media was prepared by treating murine splenocytes with HTN stimuli. (3) Results: HTN stimuli had no direct effect on hLEC or mLEC proliferation. Treatment of hLECs with HTN stimuli increased the number of lumen-forming structures and invasion distance (both p < 0.05) in the 3-D matrix but decreased the average lumen diameter and the number of cells per invading structure (both p < 0.05). Conditioned media from HTN-stimuli-treated splenocytes significantly attenuated the decrease in sprout number (aside from salt) and sprout length of mouse mesometrial LVs that is found in the HTN stimuli alone. (4) Conclusions: These data indicate that HTN stimuli indirectly prevent a decrease in lymphangiogenesis through secreted factors from HTN-stimuli-treated immune cells.

SUBMITTER: Wilcox B

PROVIDER: S-EPMC9315625 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Metastatic melanoma is an aggressive tumor and can constitute a real therapeutic challenge despite the significant progress achieved with targeted therapies and immunotherapies, thus highlighting the need for the identification of new therapeutic targets. Adrenomedullin (AM) is a peptide with significant expression in multiple types of tumors and is multifunctional. AM impacts angiogenesis and tumor growth and binds to calcitonin receptor-like receptor/receptor activity-modifying protein 2 or 3 (CLR/RAMP2; CLR/RAMP3). In vitro and in vivo studies were performed to determine the functional role of AM in melanoma growth and tumor-associated angiogenesis and lymphangiogenesis. In this study, AM and AM receptors were immunohistochemically localized in the tumoral compartment of melanoma tissue, suggesting that the AM system plays a role in melanoma growth. We used A375, SK-MEL-28, and MeWo cells, for which we demonstrate an expression of AM and its receptors; hypoxia induces the expression of AM in melanoma cells. The proliferation of A375 and SK-MEL-28 cells is decreased by anti-AM antibody (αAM) and anti-AMR antibodies (αAMR), supporting the fact that AM may function as a potent autocrine/paracrine growth factor for melanoma cells. Furthermore, migration and invasion of melanoma cells increased after treatment with AM and decreased after treatment with αAMR, thus indicating that melanoma cells are regulated by AM. Systemic administration of αAMR reduced neovascularization of in vivo Matrigel plugs containing melanoma cells, as demonstrated by reduced numbers of vessel structures, which suggests that AM is one of the melanoma cells-derived factors responsible for endothelial cell-like and pericyte recruitment in the construction of neovascularization. In vivo, αAMR therapy blocked angiogenesis and lymphangiogenesis and decreased proliferation in MeWo xenografts, thereby resulting in tumor regression. Histological examination of αAMR-treated tumors showed evidence of the disruption of tumor vascularity, with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. The expression of AM by melanoma cells promotes tumor growth and neovascularization by supplying/amplifying signals for neoangiogenesis and lymphangiogenesis.

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Hypertensive Stimuli Indirectly Stimulate Lymphangiogenesis through Immune Cell Secreted Factors

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