No Effect of Skin Lymphangiogenesis on Blood Pressure in Mouse Models of Salt‐Sensitive Hypertension

Abstract

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.

Lymphatics and Blood Pressure

“…The lymphatics move fluid from the interstitial spaces surrounding tissues to the plasma and transport immune cells to and from lymph nodes. 1,2 An original study published in this issue of Hypertension 3 investigated the potential role of dermal lymphatics in the development of salt-sensitive hypertension. The rationale for this work arises from a series of intriguing observations made in the past 2 decades, which indicated that sodium homeostasis may be regulated in part by processes dependent upon lymphatic vessels in the skin.…”

“…7,8 Despite these compelling observations, a causal link between skin lymphatics and blood pressure has not been established. To test this question, Thowsen et al 3 performed experiments to test the hypothesis that a reduction of dermal lymphatics would enhance salt-sensitive hypertension while an increase in skin lymphatics would protect from salt-sensitive hypertension.…”

“…To directly address the role of lymphatics in salt-sensitive hypertension, 3 separate strains of mice with absent, hypoplastic, or hyperplastic dermal lymphatics were established and studied. 3 The development of salt-sensitive hypertension was assessed in these mice and their wild type controls when groups of animals were separately administered each of the following chronic treatments: (1) high salt (4% NaCl) chow, (2) deoxycorticosterone acetate (DOCA) plus 1% NaCl drinking water, or (3) a nitric oxide inhibitor followed by the high salt diet. Arterial blood pressure and tissue sodium content were assessed as experimental endpoints in these animals.…”