(4db) Engineering in the Microvasculature: The Mechanical Microenvironment's Control of Systemic Metabolism

Lying between the endothelial beds of the body's circulation is the interstial microenviroment wherein the complex biohphysical and biochemical interplay of cells, the extracellular matrix, and the molecules of interstital fluid control both immediate tissue homeostasis and systemic functions. The modulators of interstitial flow rates and shear, tissue hydration and composition, and cellular trafficking are the endothelial microvasculature of the blood and venous capillaries and the lymphatic system.

In my previous studies, we demonstrated that the primary modulator of interstitial drainage, the initial lymphatic vascualture, both controls the interstitim and cells found within and is itself modulated by the tissue mechnical environment. Generation of new functional lymphatic capiallaries, lymphangiogenesis, was found to be directional and fully dependent on interstitial flow. Blocked lymphatic drainage, clinically the pathology of lymphedema, resulted in hyperproliferation, yet poor organization and decreased function of lymphatic capillaries. In the pathology of lymphedema, where intersitial flow rates slow towards zero, inflammatory chemokines accumulated, interstitial immune cells failed to traffick, and adipose tissue depots expanded in adipogenesis. Indeed, we quantified lymphatic clearance rates in genetic models of lymphatic dysfunction and found a correlation with fluid transport and remodeling of the extracellular matrix and adipose expansion on tissue hydraulic conductivities and subsequent treatment and potential resolution of the disease. Blood capillary extravasation, as controlled by Starling's Law, was reduced in these instances due to the increased hydraulic and osmotic pressures of the interstitum. Concurrently, adipose expansion or hypercholesterolemia strongly reduced lymphatic drainage capability by inducing vessel degeneration. As lymphatic vessels are the primary route of lipid transport throughout the body, these studies combined to demonstrate the potential that the interplay of microvasculature cells with their surrounding tissues has to influence systemic metabolism.

My current research focuses on adipose tissue physiology and how the microvasculature may control its systemic functions via adipokine transport. The adipokine adiponectin has exhibited positive effects in regulation of systemic metabolism and insulin sensitivity through tissues such as liver, skeletal muscle, and centrally in the brain. We have recently demonstrated oligomer size-dependence on adiponectin clearance. The molecular transport sizes, particularly that of the high molecular weight form, present transport limitations across endothelial barriers with low intercellular permeabilities such as in muscle or in the brain. We have quantified size dependent exclusion of adiponectin oligomers in model endothelial cells in vitro and using genetic mouse models of receptor deletion in vivo to discern that oligomer function likely depends on microvasculature permeabilities. In chronic kidney disease, a common co-pathology of metabolic syndrome and obesity, we demonstrate peripheral effects of renal dysfunction in adipose tissue. Current studies are aimed at discerning the interplay between these two tissues and how renal and adipose endothelial functions affect their axis of communication. The biophysical environment of adipose tissue, such as matrix composition, interstitial flow, and lymphatic drainage, may influence adipocyte behaviors, and changes in cell infiltration and chemokine levels in the interstitial fluid have a direct effect on adipogenesis and metabolic lipid fluxes.

Miteva DO, Rutkowski JM, Dixon JB, Kilarski W, Shields JD, Swartz MA. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ Res. 2010 Mar 19;106(5):920-31.

Rutkowski JM, Markhus CE, Gyenge CC, Alitalo K, Wiig H, Swartz MA. Dermal matrix remodeling and fat accumulation control tissue swelling and hydraulic conductivity during murine primary lymphedema. Am J Pathol. 2010 Mar;176(3):1122-9.

Rutkowski JM, Davis KE, Scherer PE. Mechanisms of bbesity and related pathologies: the macro- and microcirculation of adipose tissue. FEBS J. 2009 Oct;276(20):5738-46.

Lim HY, Rutkowski JM, Helft J, Reddy ST, Swartz MA, Randolph GJ, Angeli VA. Hypercholesterolemic mice exhibit lymphatic vessel dysfunction and degeneration. Am J Pathol. 2009 Sep;175(3):1328-37.

Goldman JG*, Rutkowski JM*, Shields JD*, Pasquier M, Cui Y, Schmökel HG, Pytowski B, Swartz MA. Co-operative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB J. 2007 Apr;21(4):1003-12. (* equal contribution)

Goldman J, Conley KA, Raehl A, Bondy DM, Pytowski B, Swartz MA, Rutkowski JM, Jaroch DB, Ongstad EL. Regulation of VEGF-C by interstitial flow. Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2176-83.

Rutkowski JM and Swartz MA. A driving force for change: Interstitial flow as a morphoregulator. Trends Cell Biol. 2007 Jan;17(1):44-50.

Rutkowski JM, Moya M, Johannes J, Goldman J, Swartz MA. Secondary lymphedema in the mouse tail: lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc Res. 2006 Nov;72(3):161-71.

Rutkowski JM, Boardman KC, Swartz MA. Characterization of lymphangiogenesis in a model of adult skin regeneration. Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1402-10.

Rutkowski JM, Santiago LY, Ben-Jebria, Ultman JS. Development of an assay for ozone-specific antioxidant capacity. Inhal Toxicol. 2003 Nov;15(13):1369-85.