Does Plasminogen Activator Inhibitor-1 Drive Lymphangiogenesis?

Abstract

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis.

Digging deeper into lymphatic vessel formation in vitro and in vivo

“…On the contrary, much less is known about the process of lymphangiogenesis occurring in pathological conditions. This study sought to define the ultrastructural features of neo-formed lymphatic vessels and exploited the attributes of two established models of inflammation accompanied by a robust lymphangiogenesis [ 35 , 36 , 40 ], and the advantage of the recently set up model of lymphatic ring assay which recapitulates all steps of sprouting lymphangiogenesis [ 38 ]. Here, we propose a model of lymphatic vessel formation through tunneling (Figure 8 ).…”

“…In the present study, ultrastructural features of neoformed lymphatic vessels have been investigated in two in vivo models and one in vitro 3D culture system: (1) the corneal lymphangiogenic assay induced by thermal cauterization of the mouse cornea [ 34 ]; (2) the lymphangioma model consisting in lymphatic cell hyperplasia induced by intra-peritoneal injection of incomplete Freund's adjuvant [ 35 - 37 ] and (3) the lymphatic ring assay which bridges the gap between in vitro and in vivo systems [ 38 , 39 ]. We provide innovative morphological data, at the ultrastructural level, demonstrating the pronounced ECM remodeling and intracellular vacuolization during the migration, alignment and organization of channels of sprouting lymphatic cells in vivo .…”

Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase

“…29,30 For ethical reasons, buprenorphine (0.05 mg/kg) was injected 1 hour before and after adjuvant injections, and every 12 hour during the first 5 days after injection. After 4 weeks, the diaphragms were harvested and used for transmission electron microscopy (TEM).…”

Thoracic involvement in generalised lymphatic anomaly (or lymphangiomatosis)

“…However, despite the absence of an ideal laboratory model for GLA, several promising in vivo models have recently been developed, as reported by ROCKSON [90]. These models include acquired lymphatic endothelial hyperplasia (attempting to reproduce the histological characteristics of human lesions in lymphangiomatosis), maldevelopment of dermal lymphatics in Wnt5a-knockout mice (showing the role this gene may have in the regulation of normal lymphangiogenesis), pulmonary lymphangiectasia induced by murine developmental VEGF-C overexpression and spheroid-based engineering of a human lymphatic vasculature in mice (a useful technique for the specific study of lymphatic development) [91][92][93][94][95].…”