Endothelial TLR4 Activation by Endogenous Ligands Contributes to Small Blood Vessels Formation in Angiolipoma

Angiolipomas are benign subcutaneous nodules characterized by the presence of mature adipocytes intermingled with cluster of small blood vessels, often displaying intraluminal fibrin microthrombi. It is known that fibrinogen and/or fibrin intraluminal and extracellular deposition during immune responses affect Endothelial Cell (EC) functioning and leukocyte trafficking. Also, it is known that Toll-Like Receptors (TLRs) are not only expressed in Immune Cells (ICs) but also in ECs and that excessive endothelial activation through TLR interactions with endogenous ligands such as fibrinogen, Heparan Sulfate Proteoglycans (HSPGs), Fibronectin (FN), Tenascin-C (TN-C), hyaluronan and galectin-3, contributes to EC dysfunction promoting endothelial proliferation, migration, apoptosis and tube-like structures formation. Nevertheless, studies involving the endothelial TLR4 activation by specific ligands and their contribution to the small blood vessels formation in angiolipoma has not been considered. Herein, we show that in angiolipoma TLR4 and some of their ligands such as fibrinogen, FN, HSPGs including agrin, perlecan and Synd-1 and galectin-3 as well as some glycoconjugates associated to these ligands including VE-cadherin, VCAM-1, ICAM-1, PECAM-1, endoglin and CD44 were immunolocalized in the ECs from the small vessels and some ICs. We propose that in angiolipoma tissues galectin-3 oligomerization upon binding to these TLR4 endogenous ligands and glycoproteins associated can lead to the formation of gal-glycan lattices on the endothelial surface that might be facilitating not only the activation of TLR4, but also contributing to the vasculature formation regulated by signaling pathways mediated by certain cytokines, chemokines and growth factors.