Nox activity of intact cells could not be recapitulated in membranes treated with NADPH. Proteomics of membranes show P450 reductase as source of NADPH-dependent signal. Microsomes overexpressing Cytochrome P450 system produce a NADPH-dependent signal. Knockout of P450 reductase (CRISPR/Cas9) abolished lucigenin signal in HEK cell membranes. Knockout of POR but not p22phox abolishes the basal and Angiotensin II-stimulated NADPH-dependent signal in SMC membranes.