Lymphedema is the clinical manifestation of impaired lymphatic transport. It remains an under-recognized and under-documented clinical condition that still lacks a cure. Despite the substantial advances in the understanding of lymphatic vessel biology and function in the past two decades, there are still unsolved questions regarding the pathophysiology of lymphedema, especially in humans. As a consequence of impaired lymphatic drainage, proteins and lipids accumulate in the interstitial space, causing the regional tissue to undergo extensive and progressive architectural changes, including adipose tissue deposition and fibrosis. These changes are also associated with inflammation. However, the temporal sequence of these events, the relationship between these events, and their interplay during the progression are not clearly understood. Here, we review our current knowledge on the pathophysiology of lymphedema derived from human and animal studies. We also discuss the possible cellular and molecular mechanisms involved in adipose tissue and collagen accumulation during lymphedema. We suggest that more studies should be dedicated to enhancing our understanding of the human pathophysiology of lymphedema to pave the way for new diagnostic and therapeutic avenues for this condition.

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe. Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression. Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis. Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis.

Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Caffeine inhibits the proliferation of vascular smooth muscle cells (VSMCs); however, little is known about the mechanism(s). Here, we demonstrated that caffeine decreased VSMC proliferation and induced autophagy in an in vivo vascular injury model of restenosis. Further, we studied the effects of caffeine in primary human and mouse aortic VSMCs and immortalized mouse aortic VSMCs. Caffeine decreased cell proliferation, and induced autophagy flux via inhibition of mTOR signaling in these cells. Genetic deletion of the key autophagic gene, ATG5, and its adaptor protein, SQSTM1/p62, showed the anti-proliferative effect by caffeine was dependent upon autophagy. Interestingly, caffeine also decreased Wntsignaling and the expression of two Wnt target genes, AXIN2 and Cyclin D1. This effect was mediated by autophagic degradation of a key member of the Wnt signaling cascade, DVL2, by caffeine to decrease Wnt signaling and cell proliferation. SQSTM1/p62, MAP1LC3B-II and Dvl2were also shown to interact with each other, and the overexpression of Dvl2 counteracted the inhibition of cell proliferation by caffeine. Taken together, our in vivo and in vitro findings have demonstrated that induction of autophagy by caffeine significantly reduced vascular restenosis.Caffeine reduced VSMC proliferation by inhibiting Wnt signaling via stimulation of autophagy.Our findings suggest that caffeine and other autophagy-inducing drugs may represent novel cardiovascular therapeutic tools to protect against restenosis after angioplasty and/or stent placement.