ERK1/2-Mediated Vasoconstriction Normalizes Wall Stress in Small Mesenteric Arteries During NOS Inhibition In Vivo

Abstract

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.

Role of extracellular signal-regulated kinases (ERK) in leptin-induced hypertension

“…Indeed, a single i.p. dose of PD98059 had no effect on blood pressure in rats treated with NO synthase inhibitor, although it reduced contractility of mesenteric arteries to which this inhibitor has easier and quick access via this route (Girardot et al, 2003). In separate experiments, we also observed no effect of a single PD98059 dose on blood pressure, aortic and renal ERK phosphorylation, and renal Na + ,K + -ATPase activity in leptin-treated rats.…”

Small Artery Remodeling and Erythrocyte Deformability in <i>L</i>-NAME-Induced Hypertension: Role of Transglutaminases

“…It leaves little doubt that the initial mode of action of L -NAME is by vasoconstriction [23,24,25], amongst others related to impaired shear stress sensing. The raised resistance vessel tone increases peripheral resistance and, through central regulation, the blood pressure.…”

Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

“…However, CSA increased only in the aorta, confirming that remodeling is heterogeneous along the vascular tree. 5 Thus, the aorta adapted to sustained pressure elevation by hypertrophic remodeling, whereas mesenteric resistance arteries underwent eutrophic remodeling. Interestingly, this heterogeneity also occurs in essential hypertension, 24,25 making the L-NAME model particularly suitable to study hypertension-induced vascular remodeling.…”

“…2 To explain this different response between large and small arteries, it is suggested that small arteries are not submitted to an augmented wall stress because they are initially constricted. [3][4][5] Thus, we hypothesized that inward eutrophic remodeling, which appears as a fixed form of vasoconstriction, could proceed through specific modifications of VSMC-matrix interactions.…”