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The Influence of Flow Mechanotransduction on Endothelial Cells in the Lymphatic Valve Sinus

Abstract
Fluid flow in the cardiovascular and lymphatic systems influences the phenotype of endothelial cells that line the interior to the vessel via mechanotransduction. Geometric features in a vessel such as curvature, bifurcation, and valves promote heterogeneous fluid flow profiles, inducing a heterogeneous endothelial phenotype within a vessel region. Certain flow conditions are associated with vascular dysfunction, and diseases such as atherosclerosis preferentially develop in areas of flow disturbance. Lymphatic vessels are highly analogous to blood vessels, although lymphatic flow characteristics and its effect on lymphatic endothelial cells (LECs) via mechanotransduction have been comparatively less examined. The most significant geometric features that influence fluid flow in lymphatic vessels are bi-leaflet valves present in each lymphangion. In the current study, fluid flow was characterized in murine lymphatic collecting vessels using fluorescent microparticles to examine the phenotypic difference of LECs exposed to physiological flow conditions in vitro. Fluid flow adjacent to the valve sinus was virtually static, while the wall of the midlymphangion experienced net-antegrade pulsatile flow with a small degree of retrograde flow. LECs were exposed to the midlymphangion flow waveform in a parallel plate flow chamber system and compared to cells cultured in static conditions. LECs exposed to static conditions demonstrated relatively increased expression of cell adhesion molecules via mRNA and protein quantification and leukocyte attracting chemokines via mRNA quantification. The increased expression of cell adhesion molecules and leukocyte attracting chemokines suggests that LECs in the sinus may adopt an inflammatory phenotype. Lymphedema is a notable condition that may result from valvular dysfunction and can significantly alter fluid flow and likely cause phenotypic changes in LECs via mechanotransduction. Characterization of the flow field in a vessel affected by lymphedema in a CLEC2-deficient mouse was found to be quasi-steady with loss of pulsatility. Lymphedema is characterized by changes in pressure, which independently influences endothelial cells (ECs). LECs were exposed in vitro to pulsatile or steady static pressure conditions without flow. Pulsatile and steady pressure chambers were constructed to emulate normal lymphatic pressure and lymphedema-like pressure waveforms, respectively. The effects of exposing LECs to steady versus pulsatile pressure of similar mean values have not previously been examined. This study demonstrated that LECs showed increased intercellular gap formation when exposed to steady pressure and steady flow, but not pulsatile pressure and pulsatile flow of similar mean values. Increased endothelial permeability in a lymphedema afflicted vessel could potentially promote lymph and antigen leakage, exacerbating the already impaired lymph transport, impairing the adaptive immune response, and inducing inflammation in the local interstitial tissue.
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