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Endogenous Renin‐Angiotensin System Activation Causes Accelerated Cerebral Vascular Dysfunction in Mice Expressing Dominant‐Negative Mutations in PPARγ in Endothelium

Abnormal activation of the renin‐angiotensin system (RAS) has been implicated in cardiovascular (CV) disease. Whereas low salt diet (LSD) may be beneficial in salt‐sensitive hypertension, it has been proposed to induce CV risk due to RAS activation. PPARγ is a ligand‐activated transcription factor which regulates the actions of angiotensin II (ANG) in the vasculature and promotes anti‐oxidant pathways. We hypothesized that endothelial PPARγ plays a protective role in the vasculature in response to RAS activation. Transgenic mice specifically expressing dominant‐negative mutation in PPARγ in the endothelium (E‐DN) were fed a LSD. Plasma renin and ANG were significantly increased in both non‐transgenic (NT) and E‐DN mice fed a LSD for 6 weeks compared with normal chow (Renin ‐ NT: 39±7 vs 20±1 ng/ml; E‐DN: 34±1 vs 16±4 ng/ml; ANG ‐ NT: 257±54 vs 47±6 pg/ml; E‐DN: 294±69 vs 63±14 pg/ml p<0.05, n=5). At baseline, vasorelaxation to acetylcholine (Ach) was not affected in E‐DN compared to non‐transgenic (NT) controls. Six weeks of LSD significantly impaired acetylcholine‐mediated relaxation in the basilar artery of E‐DN but not in NT (33±5 vs 69±2%, p<0.05, n=6). Unlike basilar artery, 6 weeks of LSD was not sufficient to induce vascular dysfunction in carotid artery or aorta of E‐DN (carotid artery: 92±6 vs 86±9%, n=5; aorta: 87±6 vs 81±5%, n=3). The endothelial dysfunction in the basilar artery of E‐DN was attenuated upon treatment with inhibitors of superoxide (improved from 29±5% to 55±6%, p<0.05, n=7) and NADPH oxidase (improved from 24±4% to 65±6%, p<0.05, n=3). Consistent with this, gene expression levels of Nox2 was elevated (2.1±0.3 vs 0.4±0.1, p<0.05, n=7) while those of antioxidant enzymes catalase and SOD3 were significantly blunted in cerebral vessels of E‐DN mice on a LSD (catalase: 0.5±0.1 vs 2.5±0.2; SOD3: 0.2±0.1 vs 1.1±0.1, p<0.05, n=7). Further, blockade of AT1 receptor using Losartan (0.6g/L drinking water for the last 3 weeks of LSD regimen) restored the endothelial function in the basilar artery of E‐DN mice fed LSD (improved from 31±5% to 64±9%, p<0.05, n=5). Simultaneous blockade of AT1 and AT2 (PD123319 10 mg/kg/day sc) receptors did not affect the improvement in ACh‐mediated relaxation (53±3 vs 23±3, p<0.05, n=4), suggesting that the restoration of endothelial function in the basilar artery of E‐DN mice upon losartan administration was not a consequence of AT2 receptor activation. Thus, interference with PPARγ in the endothelium produces endothelial dysfunction in the cerebral circulation in response to LSD‐mediated activation of the endogenous RAS and this dysfunction is mediated, at least in part, through AT1 receptor activation and perturbed redox homeostasis. Moreover, our data suggest that the basilar artery and perhaps cerebral circulation is particularly sensitive to inhibition of PPARγ activity and RAS activation.