Objective— A commonly accepted pivotal mechanism in fluid volume and blood pressure regulation is the parallel relationship between body Na + and extracellular fluid content. Several recent studies have, however, shown that a considerable amount of Na + can be retained in skin without commensurate water retention. Here, we asked whether a salt accumulation shown to result in VEGF (vascular endothelial growth factor)-C secretion and lymphangiogenesis had any influence on lymphatic function. Approach and Results— By optical imaging of macromolecular tracer washout in skin, we found that salt accumulation resulted in an increase in lymph flow of 26% that was noticeable only after including an overnight recording period. Surprisingly, lymph flow in skeletal muscle recorded with a new positron emission tomography/computed tomography method was also increased after salt exposure. The transcapillary filtration was unaffected by the high-salt diet and deoxycorticosterone-salt treatment, suggesting that the capillary barrier was not influenced by the salt accumulation. A significant reduction in lymph flow after depletion of macrophages/monocytes by clodronate suggests these cells are involved in the observed lymph flow response, together with collecting vessels shown here to enhance their contraction frequency as a response to extracellular Na + . Conclusions— The observed changes in lymph flow suggest that the lymphatics may influence long-term regulation of tissue fluid balance during salt accumulation by contributing to fluid homeostasis in skin and muscle. Our studies identify lymph clearance as a potential disease-modifying factor that might be targeted in conditions characterized by salt accumulation like chronic kidney disease and salt-sensitive hypertension.

Background: Recent studies have indicated that sodium storage is influenced by macrophages that secrete VEGF-C (vascular endothelial growth factor) during salt stress thus stimulating lymphangiogenesis, thereby acting as a buffer against increased blood pressure (BP). We aimed to explore the role of dermal lymphatics in BP and sodium homeostasis. Our hypothesis was that mice with reduced dermal lymphatic vessels were more prone to develop salt-sensitive hypertension, and that mice with hyperplastic vessels were protected. Methods: Mice with either hypoplastic (Chy), absent (K14-VEGFR3 [vascular endothelial growth factor receptor 3]-Ig), or hyperplastic (K14-VEGF-C) dermal lymphatic vessels and littermate controls were given high-salt diet (4% NaCl in the chow), deoxycorticosterone acetate (DOCA)-salt diet and 1% saline to drink or nitric oxide blocker diet L-N G -nitro arginine methyl ester (followed by high salt diet). BP was measured by telemetric recording, and tissue sodium content by ion chromatography. Results: In contrast to previous studies, high salt diet did not induce an increase in BP or sodium storage in any of the mouse strains investigated. DOCA-salt, on the other hand, gave an increase in BP in Chy and K14-VEGFR3-Ig not different from their corresponding WT controls. DOCA induced salt storage in skin and muscle, but to the same extent in mice with dysfunctional lymphatic vessels and WT controls. Lymph flow as assessed by tracer washout was not affected by the diet in any of the mouse strains. Conclusions: Our results suggest that dermal lymphatic vessels are not involved in salt storage or blood pressure regulation in these mouse models of salt-sensitive hypertension.

An expanded lymphatic network is capable of enhanced chemoattractant production, and lymphangiogenesis will facilitate initial lymph formation favoring increased clearance of fluid in situations of augmented fluid filtration.

The pathogenesis of hypertension is not well understood, but high sodium intake has been associated with blood pressure (BP) rise. Studies have indicated that sodium can be stored in skin without commensurate water accumulation, and macrophages may secrete VEGF‐C that can stimulate lymphangiogenesis, thereby acting as a buffer against increased BP. Here we aimed to explore the role of dermal lymphatics in BP and sodium homeostasis. Our hypothesis was that mice with reduced dermal lymphatic vessels were more prone to develop salt‐sensitive hypertension, and that mice with hyperplastic vessels were protected against this outcome. Mice with either absent (K14‐VEGFR3‐Ig), hypoplastic (Chy) or hyperplastic (K14‐VEGF‐C) dermal lymphatic vessels and littermate controls were given high salt diet (HSD) (4% NaCl in the chow and 1% saline to drink), DOCA‐salt diet (16mg/week 11‐deoxycorticosterone acetate ‐ 50mg/21 days slow release tablet subcutaneously and 1% saline to drink) or nitric oxide (NO) blocker diet (L‐NAME 0.5mg/ml in drinking water for 3 weeks, followed by one week washout and thereafter 2 weeks HSD). BP was measured by telemetric recording, and tissue sodium content by ion chromatography. In contrast to previous studies, HSD did not induce an increase in BP or sodium storage in any of the mouse strains investigated. DOCA‐salt, on the other hand, induced an increase in mean arterial pressure (MAP) in Chy of 13.4 ± 7.1 (SD) mm Hg (n=4), not different from a corresponding pressure in WT control of 14.7 ± 6.4 mm Hg, n=5. In K14‐VEGFR3‐Ig mice, DOCA raised the MAP 24 ± 12.1 mm Hg (n=6), not different from the corresponding WT control (22.8 ± 8.3 mm Hg, n=7). DOCA induced salt storage in skin and muscle, but to the same extent in mice with dysfunctional lymphatic vessels and WT controls. L‐NAME diet tended to give a higher diastolic pressure in mice lacking dermal lymphatic vessels compared with WT control as suggested by the rise in diastolic BP of 11.6 ± 10.8 (SD) mm Hg (n=9) and 1.9 ± 2.4 (SD) mm Hg (n=6) (p<0.05, One‐way ANOVA), respectively, without a concomitant increase in sodium content in skin or muscle in any of the strains. Our results indicate that there is no association between dermal lymphangiogenesis, sodium accumulation and blood pressure response. The response seen in NO‐blocker diet in mice lacking dermal lymphatic vessels was salt storage independent. This suggests that dermal lymphatic vessels are not involved in salt storage or blood pressure regulation in these mouse models of salt‐sensitive hypertension.