Doxorubicin suppression of lymphatic function and therapeutic reversal

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 DESCRIPTION (provided by applicant): More than 5 million women in the United States suffer from arm lymphedema after surgery and/or radiation for breast cancer, and the incidence and severity of lymphedema is worsened by doxorubicin (DOX) chemotherapy. The mechanism by which DOX contributes to lymphedema is poorly understood, but it is thought to involve multiple mechanisms of acute and delayed injury to the lymphatic system due to its cytotoxic effects. Alternatively, in this proposal, we will explore the hypothesis that DOX acutely and directly suppresses lymphatic contractile function and DOX-induced suppression of lymphatic flow can be reversed by pharmacological openers of voltage-gated L-type Ca2+ (CaL) channels. Using the rat mesenteric lymphatic system as our model, we will show for the first time that DOX at clinically relevant concentrations directly suppresses the spontaneous contractions ("pumping") of lymph vessels, which propel extracellular fluid from peripheral tissues to the central veins to prevent lymphedema. The spontaneous contractions of lymph vessels rely on Ca2+ influx through CaL channels, and DOX-induced suppression of lymphatic contractions can be partly reversed by CaL channel openers. Based on these findings, we propose to i) define the direct effect of DOX on the contractile activity of isolated lymph vessels, ii) use patch-clamp techniques to determine if DOX blocks CaL channels in lymphatic smooth muscle cells, and iii) use in vivo flow cytometry with high-resolution intravital optical imaging to define the acute effet of DOX chemotherapy on in vivo lymphatic flow.