Angiotensin II-induced Hypertension is Reduced by Deficiency of P-selectin Glycoprotein Ligand-1

Abstract

Identification of inflammatory mediators that regulate the vascular response to vasopressor molecules may aid in the development of novel therapeutic agents to treat or prevent hypertensive vascular diseases. Leukocytes have recently been shown to be capable of modifying blood pressure responses to vasopressor molecules. The purpose of this study was to test the hypothesis that deficiency of the leukocyte ligand, Psgl-1, would reduce the pressor response to angiotensin II (Ang II). Mice deficient in Psgl-1 (Psgl-1^-/-) along with wild-type (WT) controls were treated for 2 weeks with a continuous infusion of Ang II. No differences in blood pressure between the groups were noted at baseline, however after 5 days of Ang II infusion, systolic blood pressures were higher in WT compared to Psgl-1^-/- mice. The pressor response to acute administration of high dose Ang II was also attenuated in Psgl-1^-/- compared to WT mice. Chimeric mice with hematopoietic deficiency of Psgl-1 similarly showed a reduced pressor response to Ang II. This effect was associated with reduced plasma interleukin-17 (IL-17) levels in Psgl-1^-/- mice and the reduced pressor response was restored by administration of recombinant IL-17. In conclusion, hematopoietic deficiency of Psgl-1 attenuates Ang II-induced hypertension, an effect that may be mediated by reduced IL-17.

Figure 1

Effect of Psgl-1 deficiency on Ang II-induced hypertension. (A) Tail-cuff measurement of systolic blood pressure of WT and Psgl-1^−/− mice in response to chronic infusion of saline or Ang II administered via osmotic minipumps (n = 10 mice per group). (B) Systolic blood pressure measured following catheterization of the carotid artery in response to chronic infusion of saline or Ang II (n = 5 mice per group). (C) Systolic blood pressure response to acute infusion of Ang II in WT and Psgl-1^−/− mice (n = 5 mice per group). (D) Diastolic blood pressure response to acute infusion of Ang II in WT and Psgl-1^−/− mice. *P < 0.05.

Figure 2

Levels of plasma factors before and after cumulative infusion of Ang II in WT and Psgl-1^−/− mice (n = 5 mice per group). (A) Levels of soluble P-selectin (sP-sel). (B) Levels of soluble E-selectin (sE-sel). (C) Levels of interleukin-17 (IL-17). *P < 0.05. **P < 0.01.

Figure 3

Pressor responses to acute infusion of Ang II after bone marrow transplantation or Psgl-1 antibody treatment (n = 5 mice per group). (A) Pooled data of systolic blood pressure response to Ang II in WT mice receiving WT bone marrow (BM) and WT mice receiving Psgl-1^−/− BM. (B) Pooled data of systolic blood pressure response to Ang II in WT mice receiving control antibody (Ab) and WT mice receiving anti-Psgl-1 Ab. *P < 0.05.

Figure 4

Levels of plasma factors after cumulative infusion of Ang II after bone marrow transplantation or Psgl-1 antibody treatment (n = 5 mice per group). (A,B,C) Levels of sP-sel (A), sE-sel (B), and IL-17 (C) in WT mice receiving WT bone marrow (BM) and WT mice receiving Psgl-1^−/− BM. (D,E,F) Levels of sP-sel (D), sE-sel (E), and IL-17(F) in WT mice receiving control Ab and WT mice receiving Psgl-1 Ab. *P < 0.05. **P < 0.01.

Figure 5

The effect of IL-17 treatment on pressor responses to Ang II in Psgl-1^−/− mice (n = 5 mice per group). Pooled data of systolic blood pressure (A), diastolic blood pressure (B), and mean arterial pressure response (C) to acute infusion of Ang II after PBS or IL-17 treatment in Psgl-1^−/− mice. *P < 0.05.