Editors' ChoicePhysiology

T Cell Activation and High Blood Pressure

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Sci. Signal.  02 Dec 2014:
Vol. 7, Issue 354, pp. ec335
DOI: 10.1126/scisignal.aaa3798

Although hypertension is a major risk factor for cardiovascular and kidney diseases and a leading cause of death worldwide, previous studies have implicated T cells and inflammatory factors, including cytokines, as contributory factors (see commentary by Tracey). Noting that the vascular endothelial growth factor (VEGF)-like angiogenic factor P1GF (placental growth factor) is produced by cells of the cardiovascular and immune systems, Carnevale et al. investigated its role in a mouse model of hypertension induced by intravenous infusion of angiotensin II (AngII). Whereas wild-type (WT) mice developed increased blood pressure in response to AngII, P1GF-deficient mice did not. In response to AngII, T cells infiltrated the blood vessels and kidneys of WT, but not P1GF-deficient, mice. In addition, AngII stimulated the production of P1GF in the spleens of WT mice; however, surgical removal of the celiac ganglion, which innervates the spleen, reduced the amount of splenic P1GF produced. Splenectomized mice were protected from AngII-induced hypertension; however, the hypertensive response was restored if they were transplanted with spleens from WT, but not P1GF-deficient, mice. Tissue inhibitor of metalloproteinases 3 (Timp3) is a factor implicated in inhibiting the activation of T cells by antigen-presenting cells. Whereas AngII had no effect on splenic Timp3 abundance in WT mice, it led to a marked increase in splenic Timp3 abundance in P1GF-deficient mice. Indeed, transgenic mice overexpressing Timp3 in macrophages were protected from AngII-induced hypertension. Further experiments showed that P1GF repressed the expression of the gene encoding Timp3 in a p53- and Sirt1-dependent manner. Together, these data suggest that the development of hypertension is mediated by a P1GF-dependent neuroimmune interaction in the spleen that activates T cells and leads to their recruitment to blood vessels and the kidneys.

D. Carnevale, F. Pallante, V. Fardella, S. Fardella, R. Iacobucci, M. Federici, G. Cifelli, M. De Lucia, G. Lembo, The angiogenic factor P1GF mediates a neuroimmune interaction in the spleen to allow the onset of hypertension. Immunity 41, 737–752 (2014). [Online Journal]

K. J. Tracey, Hypertension: An immune disorder? Immunity 41, 673–674 (2014). [Online Journal]