Abstract-Although conduit arteries develop hypertrophy after chronic NO synthesis blockade, resistance arteries remodel without hypertrophy under the same conditions. Similar findings have been described in essential hypertension. We postulated that this regional difference may be related to a heterogeneous effect of endogenous NO on proliferation along the vascular tree. Newly synthesized proteins were radiolabeled in vivo with [ 3 H]L-leucine in basal conditions and during NO synthase inhibition, with or without PD98059 (inhibitor of the extracellular signal-regulated kinases [ERK] 1/2). Blocking the generation of NO by 3 different L-arginine analogues increased protein synthesis by an average of 75% in the aorta, in association with enhanced ERK 1/2 phosphorylation. PD98059 significantly reduced L-arginine analogue-induced protein synthesis and ERK 1/2 phosphorylation, confirming the involvement of ERK 1/2 as an important signaling element. In small arteries, L-arginine analogues did not influence the extent of protein synthesis, although phosphorylation of ERK 1/2 was also enhanced. To determine the role of NO in a condition of enhanced protein synthesis, angiotensin II was infused for 24 hours. Angiotensin II augmented protein synthesis in mesenteric arteries and the aorta, and was additive to NO synthase blockade in the aorta. In conclusion, endogenous NO exerts a tonic inhibitory influence on aortic growth, with limited impact on small arteries in basal and hypertrophic conditions. This heterogeneous role of NO on vascular growth may explain the heterogeneity of vascular remodeling observed in essential hypertension, a condition associated with endothelial dysfunction. Key Words: hypertrophy Ⅲ nitric oxide Ⅲ nitric oxide synthase Ⅲ kinase Ⅲ arteries Ⅲ aorta T he endothelium is an important modulator of vascular reactivity and structure, and NO is one of the main products synthesized and released by endothelial cells. 1 Most of the biological effects of NO are mediated by cGMP and include regulation of vascular tone and endothelial permeability, inhibition of platelet adhesion and aggregation, and inhibition of leukocyte-endothelial cell interactions. 2 In addition, early studies in vascular smooth muscle cells (VSMCs) in culture have shown that NO donors inhibit cellular proliferation 3,4 (for review, see Sarkar and Webb 5 and Jeremy et al 6 ), which is an important event in the pathogenesis of atherosclerosis, restenosis, and possibly hypertension. 7 Among the signaling pathways related to NO inhibition of cell proliferation, inhibition of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation has been proposed to be important, considering the pivotal role of this signaling event in VSMC growth. 6,8 In hypertension, arteries adapt to the pressure-induced elevation in wall stress by changing their geometry. 9,10 Indeed, the elevated vascular resistance observed in hypertension is associated with an increased media thicknesslumen diameter ratio (remodeling) of resistance arteries. 11,12 In essenti...

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As in essential hypertension, chronic nitric-oxide synthase (NOS) inhibition leads to hypertrophic remodeling in conduit and muscular arteries and inward eutrophic remodeling in small resistance arteries with activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in both vessel types. The authors tested the hypothesis that this remodeling heterogeneity could be related to distinct vasoreactivity patterns in small and larger arteries, with a vessel-specific function of ERK1/2 signaling. Using intravital microscopy in rats we have demonstrated that acute NOS inhibition (l-NA injection, 100 mg/kg) produced vasoconstriction of small mesenteric arteries. Consequently, the calculated in vivo wall stress was not significantly modified, despite the local rise in pressure. This could explain the lack of vascular protein synthesis elevation in vivo, an early index of hypertrophy. Inhibition of ERK1/2 activation with PD98059 blunted mesenteric artery contractions. Femoral arteries did not contract and were thus submitted to an enhanced wall stress and underwent hypertrophic remodeling in chronic conditions. In conclusion, the heterogeneous vascular remodeling in the l-NAME model is associated with a heterogeneous vasoconstriction response to acute NOS inhibition. Indeed, in contrast to larger arteries, l-NA-induced vasoconstriction in small arteries normalized wall stress and prevented early signs of hypertrophy. The results also suggest that ERK1/2 is a signaling element in NOS inhibition-induced vasoconstriction of small arteries in vivo.

Omapatrilat and lisinopril regressed coronary remodelling and cardiac collagen deposition, and reduced vascular oxidative stress in DOCA-salt hypertensive rats. However, despite similar antihypertensive efficacy, omapatrilat was superior to lisinopril in improving the endothelial-dependent coronary dilatation, suggesting a better vascular protection in the DOCA-salt model of hypertension.