Chronic metabolic stress impairs lymphatic contractility via activation of KATP channels in a mouse model of Type-2 diabetes.

Introduction: Chronic metabolic stress is a common underlying factor of multiple diseases, including obesity, type II diabetes, and metabolic syndrome. Lymphatic dysfunction, including valve defects, impaired contractile activity, and hyperpermeability, is also associated with these same diseases. We recently reported that acute metabolic stress leads to activation of KATP channels in lymphatic muscle cells, resulting in impairment of the intrinsic lymphatic pacemaker that drives their spontaneous contractions and active lymphatic pumping. Methods: In the present study, we tested whether lymphatic contractile dysfunction occurs in the db/db mouse, a model of metabolic syndrome, and, if so, to what extent dysfunction might be mediated by KATP channel activation. Contractile function was assessed Results: Vessels from db/db mice exhibited pressure-dependent spontaneous contractions that were significantly reduced in amplitude, frequency, and calculated fractional pump flow at all tested pressures in the range 0.5 to 5 cmH Discussion: Our results suggest that a substantial fraction of lymphatic contractile impairment in db/db mice is mediated by the activation of KATP channels in lymphatic muscle cells, in part due to chronic metabolic stress associated with elevated glucose.