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Presenter: Gina T Farias-Eisner
Co-Authors: Aschen SZ; Weitman ES; Cuzzone DA; Albano NJ; Ghanta S; Mehrara BJ
Memorial Sloan Kettering Cancer Center

Introduction: Although it is clear that cell cycle regulation and differentiation are critical steps in lymphangiogenesis, the mechanisms that regulate this process remain unknown. Previous studies have shown that P21 expression is an important regulator of endothelial cell proliferation secondary to vascular injury. Therefore, the purpose of these studies was to test the hypothesis that p21 plays a similar role in orchestrating physiologic and inflammatory lymphangiogenesis.

Methods: We used a well-described inflammatory lymph node model in p21 wild-type and knock out (KO) mice in order to determine how p21 coordinates inflammatory lymphangiogenesis. We also used a mouse-tail model of lymphedema in these same animals to determine the effect of p21 expression on lymphangiogenesis during wound repair and in response to lymphatic fluid stasis.

Results: Comparison of inflamed and control lymph nodes in wild-type mice demonstrated a marked decrease in p21 expression and concomitant increase in lymphangiogenesis in inflamed lymph nodes (both p<0.01). In addition, loss of p21 expression in p21KO mice resulted in significantly increased inflammatory lymphangiogenesis as compared with wild-type controls (p<0.05). Interestingly, we found that the expression of p21 was markedly (10-fold) increased in response to lymphatic fluid stasis when the superficial and deep lymphatic vessels were disrupted in the mouse-tail. This finding correlated with impaired lymphatic repair across the wound and lymphatic fluid stasis when compared to animals with tail incision without deep lymphatic ligation.

Conclusions: We show for the first time that p21 is a critical regulator of cell cycle progression in lymphangiogenesis during wound repair and inflammation. These findings have clinical implications suggesting that p21 can act both as a regulator of lymphangiogenesis and respond to aberrant proliferation in lymphatic endothelial cells. Thus, P21 may serve as a potential therapeutic target for a wide variety of lymphatic disorders including lymphatic malformations, lymphedema, and tumor lymphangiogenesis.

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