Uncovering Endothelium‐Dependent Mechanisms of Lymphatic Dysfunction in Obesity
Authors: Castorena-Gonzalez Jorge A. , Li Min , Davis Michael J. 
Published: April 2020

Obesity and type‐2 diabetes are major risk factors for the development of cardiovascular diseases. While evidence of lymphatic dysfunction has been reported in obese and/or diabetic patients, the mechanisms underlying that dysfunction are unknown. Efficient lymph transport relies on the intrinsic spontaneous contractions of collecting lymphatics and one‐way check valves that prevent or minimize backflow. Lymphatic contractions are initiated by action potentials that originate at a pacemaking site and then rapidly propagate between the strongly‐coupled lymphatic muscle cells (LMCs). We recently showed that in healthy lymphatics, electrical coupling between LMCs and lymphatic endothelial cells (LECs) appears to be quite limited, in contrast with strong coupling through myoendothelial junctions (MEJs) in arterioles. This apparent electrical isolation of LMCs from other surrounding cell networks may not only be a unique feature of the lymphatic vasculature, but it may be essential for the focal generation of pacemaking currents and their efficient propagation solely along the LMC‐layer. Therefore, we hypothesize that electrical coupling between LMCs and other cells can be abnormally enhanced in certain disease states that involve modifications to the extracellular matrix scaffold leading to abnormal cellular adhesion and abnormal cellular interactions. In particular, enhanced electrical coupling of LMCs and LECs could result in impaired lymphatic contractile function as a consequence of aberrant propagation of pacemaking signals. Lymphatic dysfunction, both contractile and valve dysfunction, could also result from increased fibrosis and stiffness in these disease states. Here we focus on the study of lymphatic dysfunction associated with obesity. Our results show that in obese mice (mice fed a Western Diet for 14 weeks), the contractile function of collecting lymphatics is impaired and lymphatic valve function decreased. While the origin for increased stiffening has not been determined, our preliminary observations point to lymphatics from obese mice being stiffer. Furthermore, PAI‐1 (Plasminogen Activator Inhibitor), a valuable biomarker in metabolic syndrome and type‐2 diabetes associated with obesity, is upregulated in the wall of lymphatic vessels from obese mice when compared to non‐obese age‐matched controls. Importantly, PAI‐1 has been shown to regulate the formation of vascular MEJs. Finally, our preliminary observations show that genetic overexpression of PAI‐1 in non‐obese mice results in apparently stiffer lymphatic vessels that display impaired contractility, while PAI‐1 deficiency appears to improve contractile function. In conclusion, our results associate obesity with lymphatic contractile dysfunction; point to a critical role for PAI‐1, which is primarily secreted by the endothelium, in regulating lymphatic function and regulating how cells interact in the lymphatic wall; and suggest the potential use of PAI‐1 as a therapeutic target to ameliorate lymphatic dysfunction associated with obesity.

Support or Funding Information

This research is supported by NIH‐1K99HL141143‐01A1 to JACG and NIH‐5R01HL125608‐02 to MJD.