T-cell-derived miRNA-214 mediates perivascular fibrosis in hypertension

RATIONALE: Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. OBJECTIVES: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. METHODS AND RESULTS: Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214^-/- prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfib1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214^-/- mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into perivascular adipose tissue was abolished in miR-214^-/- mice. Adoptive transfer of miR-214^-/- T cells into RAG1^-/- mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II nduced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214^-/-. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214^-/- prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-a, IL-9, and IFN-y) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. CONCLUSIONS: T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release.