Fibroblast Nox2 (NADPH Oxidase-2) Regulates ANG II (Angiotensin II)–Induced Vascular Remodeling and Hypertension via Paracrine Signaling to Vascular Smooth Muscle Cells

Objective: The superoxide-generating Nox2 (NADPH oxidase-2) is expressed in multiple cell types. Previous studies demonstrated distinct roles for cardiomyocyte, endothelial cell, and leukocyte ANG II (angiotensin II)–induced cardiovascular remodeling. However, the vivo role of fibroblast remains unclear. Approach Results: We developed a novel mouse model with inducible fibroblast-specific deficiency (fibroblast-specific knockout or Fibro-Nox2KO mice) investigated responses to chronic stimulation. mice showed no differences basal blood pressure vessel wall morphology, but hypertensive response infusion (1.1 mg/[kg·day] 14 days) was substantially reduced as compared control Nox2-Flox littermates. This accompanied by significant attenuation aortic resistance conditioned medium II–stimulated primary fibroblasts induced increase vascular smooth muscle growth, which inhibited short hairpin RNA (shRNA)-mediated knockdown Nox2. Mass spectrometric analysis secretome II–treated identified GDF6 (growth differentiation factor 6) potential growth that may be involved these effects. Recombinant concentration-dependent while significantly increased protein levels not animals. Finally, silencing prevented induction fibroblast-conditioned media vitro. Conclusions: These results indicate plays crucial development II–induced remodeling hypertension vivo. Mechanistically, regulate paracrine signaling medial cells via factors, such GDF6.