Genetic Engineering of Lymphangiogenesis in Skin Does Not Affect Blood Pressure in Mouse Models of Salt-Sensitive Hypertension

Abstract

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.

Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases

“…Interestingly, a recent report from Helge Wiig’s group using mice with either hypoplastic (Chy), absent (K14-VEGFR3), or hyperplastic (K14-VEGF-C) dermal lymphatic vessels and littermate controls demonstrated lymphatic vessels in skin have minimal impact on blood pressure regulation when the mice were fed with high-salt diet (ie, 4% NaCl in the chow). 103…”

Intestinal Lymphatic Dysfunction in Kidney Disease

“…159,171,172 Depletion of mononuclear phagocytes or blockade of VEGFC during high salt intake increased density and hyperplasia of lymphatic capillaries in the skin in association with hypertension, although recent studies from the same groups have questioned the singular effect of lymphangiogenesis on blood pressure. 159,171,173 It is, therefore, notable that aside from lymphatic growth, sodium can also modulate lymphatic dynamics, which may have a role in hypertension and other diseases. 5,174,175 Mizuno et al 175 showed high-sodium diet suppressed the amplitude, ejection fraction, and stroke volume that markedly reduced pumping activity in afferent lymphatics while efferent lymphatics were resistant to the effects high-salt diet and preserved pumping reflected increased contraction frequency.…”

Novel avenues to control blood pressure: targeting the renal lymphatic system

“…Renal lymphangiogenesis has been suggested as a pathway to decrease blood pressure levels in mice [ 16 ]. This seems to be an organ-specific phenomenon as skin lymphangiogenesis does not alter blood pressure during salt-induced hypertension [ 17 ]. In the present study, mice-deficient in dermal lymphatics (K14-VEGFR3), or with increased dermal lymphatic vessels (K14-VEGF-C) were exposed to high-salt diet or DOCA+ L-NAME + high-salt diet models of hypertension.…”