Vascular Sphingosine Kinase 1 Regulates Angiotensin II-Induced Hypertension

S1P (sphingosine-1-phosphate) signaling plays a key role in regulating the cardiovascular system. In experimental essential hypertension (HTN), expression of Sphk1 (sphingosine kinase 1), a key S1P-producing enzyme, is upregulated in the vasculature. Mice with global Sphk1 deletion exhibit alleviated AngII (angiotensin II)-induced HTN. However, cellular mechanisms underlying this protective effect remain unclear due to pleiotropic S1P actions.

Mice with targeted deletion of Sphk1 in smooth muscle cells (SMCs) or endothelial cells were generated using the Cre-loxP system. To induce HTN, mice were infused with AngII (490 ng/min per kilogram for 14 days), using osmotic minipumps. Blood pressure was monitored, and vascular structure and function were assessed ex vivo using wire/pressure myography and histological analysis. To identify mechanistic pathways, RNA sequencing was performed on mouse aortas and mesenteric arteries, followed by Gene Set Enrichment Analysis and validation by RT-qPCR/Western blotting.

SMC-specific deletion of Sphk1 conferred significant protection against HTN (mean systolic blood pressure±SD, 131.5±14.6 versus 168.3±14.3 mm Hg in WT^f/f control, P<0.05). Endothelial cell-specific Sphk1 knockout developed HTN comparable to WT^f/f. Reduced systolic blood pressure in AngII-infused SMC knockout-Sphk1 was linked to reduced myogenic tone and decreased expression of Rock1/2 (Rho-associated protein kinase 1 and 2) in mesenteric arteries. Despite protection from HTN, mesenteric arteries of AngII-infused SMC knockout-Sphk1 mice were stiffer and exhibited impaired vasorelaxation, associated with excessive Fn1 (fibronectin 1) deposition. An inverse correlation between FN1 and SPHK1 protein expression was also observed in human arteries. Notably, these arterial alterations were absent in normotensive SMC knockout-Sphk1 mice.

SMC-derived Sphk1 plays a predominant role in AngII-induced HTN by modulating myogenic tone.