Amelioration of salt-induced vascular dysfunction in mesenteric arteries of Dahl salt-sensitive rats by missense mutation of extracellular superoxide dismutase

Abstract

Superoxide dismutase (SOD) enzymes, including extracellular SOD (ecSOD), are important for scavenging superoxide radicals (O2(·-)) in the vasculature. This study investigated vascular control in rats [SS-Sod(3m1Mcwi) (ecSOD(E124D))] with a missense mutation that alters a single amino acid (E124D) of ecSOD that produces a malfunctioning protein in the salt-sensitive (Dahl SS) genetic background. We hypothesized that this mutation would exacerbate endothelial dysfunction due to elevated vascular O2(·-) levels in SS, even under normal salt (NS; 0.4% NaCl) conditions. Aortas of ecSOD(E124D) rats fed standard rodent chow showed enhanced sensitivity to phenylephrine and reduced relaxation to acetylcholine (ACh) vs. SS rats. Endothelium-dependent dilation to ACh was unaffected by the mutation in small mesenteric arteries of ecSOD(E124D) rats fed NS diet, and mesenteric arteries of ecSOD(E124D) rats were protected from endothelial dysfunction during short-term (3-5 days) high-salt (HS; 4% NaCl) diet. ACh-induced dilation of mesenteric arteries of ecSOD(E124D) rats and SS rats fed NS diet was inhibited by N(G)-nitro-l-arginine methyl ester and/or by H2O2 scavenging with polyethylene glycol-catalase at higher concentrations of ACh. Total SOD activity was significantly higher in ecSOD(E124D) rats vs. SS controls fed HS diet, most likely reflecting a compensatory response to loss of a functional ecSOD isoform. These findings indicate that, contrary to its effect in the aorta, this missense mutation of ecSOD in the SS rat genome has no negative effect on vascular function in small resistance arteries, but instead protects against salt-induced endothelial dysfunction, most likely via compensatory mechanisms involving an increase in total SOD activity.

High Sodium Intake Impairs Small Artery Vasoreactivity in vivo in Dahl Salt-Sensitive Rats

“…However, the main artery and the distributing arteries play a much smaller role in maintaining peripheral vascular resistance when compared with the small arteries. Additionally, with isolated vessels perfused with Krebs buffer or physiological salt solution in vitro [22, 23], the state of the vessels and their responses to various agents are not comparable to those in vivo, with regular blood perfusion and an intact nervous reflex system. Therefore, an overwhelming majority of previous studies dealing with vascular function have failed to maintain a physiological environment and to focus on resistant arteries because of the limitations of experimental conditions.…”

“…Since the characteristics of these inbred rats tend to be very consistent, we still obtained meaningful results. In previous studies with DS rats, a similar sample size was used [23, 41]. Second, the conclusions drawn from an animal study cannot be simply extrapolated to humans.…”

Endothelial dysfunction and vascular disease - a 30th anniversary update

“…, Beyer et al . ). This endothelial dysfunction can be prevented by antihypertensive therapy (Lüscher et al .…”

“…), missense mutation of extracellular SOD (Beyer et al . ), or by chronic activation of transient receptor potential vanilloid type 1 (TRPV1) channels with capsaicin (Hao et al . ).…”

“…); (vi) missense mutation of extracellular SOD (Beyer et al . ); (vii) heterogenous deletion of GRK2 (Avendano et al . ); (viii) deletion of caveolin‐1 (Rath et al .…”