Abstract
Post-occlusive reactive hyperemia (PORH) is a physiological reaction characterizing the vascular reactivity to application and cessation of blood flow occlusion. Increasing evidence indicates that the PORH may reduce tumor hypoxia and could be used as a clinically relevant method to improve the efficiency of conventional anti-cancer therapies. In order to experiment this new concept, we developed a simple and reproducible mouse model of skin PORH using a leg tourniquet to produce temporary vascular occlusion. Footpad superficial perfusion was continuously measured by laser speckle contrast imaging. We then analyzed the incidence of PORH on B16-F10 melanomas cells injected in the footpad skin. The mouse model reproduced the characteristics of the skin PORH in humans, with a close relationship between the duration of the vascular occlusion and the hyperemia amplitude as well as extent. We also unravelled that PORH also occurred in growing melanoma with a significant 48% median hyperemia after three minutes of vascular occlusion. We therefore described for the first time a PORH phenomenon in a locally very advanced and necrotic murine melanoma that may pave the way for the development of complementary therapeutic approaches to dampen the growth of aggressive tumors.
Highlights
We unravelled that Post-occlusive reactive hyperemia (PORH) occurred in growing melanoma with a significant 48% median hyperemia after three minutes of vascular occlusion
Post- occlusive reactive hyperemia study in footpad healthy skin: In a second step, we studied the healthy skin reaction to leg vascular occlusion through tourniquet, and the influence of the occlusion time (30 seconds or 3 minutes of occlusion) on the characteristics of PORH assessed by laser speckle contrast imaging
Post-occlusive reactive hyperemia values increased with vascular occlusion duration, as in human skin PORH (Figure 5, Table 2)
Summary
Tumor angiogenesis [1] leads to pathological, dilated and tortuous vascular network [2,3], that causes abnormal perfusion of the hypoxic tumor area [4,5], leading to, at least in part, resistance to conventional anti-cancer therapies [6,7,8].Post-occlusive reactive hyperemia (PORH) is an ubiquitous physiological vascular reaction [9,10], first described in the skin [11], that consists of a hyperemia peak, occurring just after the release of a temporary vascular occlusion, followed by a progressive return to the pre-occlusion perfusion level. Since tumor blood vessels are mostly functional and sensitive to vasoactive agents [12,13,14], one can speculate that PORH could increase tumor perfusion. In this line, PORH has been recently described as a mean to enhance temporary and locally the tumor perfusion and oxygenation levels increasing the outcome of anticancer therapies in human [15]. Tumor PORH has been recently demonstrated in human basal cell carcinoma [16]. LSCI may provide a valuable tool to develop our knowledge of tumor PORH phenomenon and therapeutic potential
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