Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease. Here, we review classical and more recent data that suggest that ET-1 should be regarded as an essential component of NO signaling. In particular, we review evidence of the role of ET-1 in models of acute and chronic NO synthase blockade. Furthermore, we discuss the possible mechanisms by which NO modulates ET-1 activity. On the basis of these studies, we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.

Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1–induced vasoconstriction compared with controls (n=7 per group; P <0.001); NO synthase inhibition with L-N ^G -nitro-arginine-methyl ester potentiated bET-1–induced vasoconstriction, albeit this effect was 2-fold greater ( P <0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n=9–11 per group). In the presence of L-N ^G -nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymostatin, the gelatinase inhibitor GM6001, or the neutral endopeptidase inhibitor thiorphan did not alter responses to bET-1; however, the ET-converting enzyme inhibitor CGS35066 almost completely abolished vascular responses to bET-1 in control and IUGR groups. Systolic blood pressure in IUGR male offspring was more responsive to ET-1 antagonism in vivo compared with controls (−9 versus −4 mm Hg; n=5 per group; P =0.02); no such differences were observed in female offspring (n=5–6 per group). These results demonstrate that vascular ET-1 function is programmed by prenatal hypoxia and provide further insights into the sex differences in the long-term vascular effects of developmental stressors.

Advanced maternal age is becoming increasingly common in Western societies and is associated with increased maternal and fetal morbidity and mortality. We hypothesized that aging results in impaired vascular function in pregnancy because of increased vascular oxidative stress and resultant scavenging of nitric oxide in both uterine and systemic arteries, causing reduced uteroplacental perfusion and poor pregnancy outcomes. Using aged rats (9.5 months), we investigated the effect of a delayed first natural pregnancy on pregnancy outcomes and uterine and mesenteric artery function on gestational day 20. Delayed pregnancy in the rat reduced fertility by 46%, reduced litter size by 36%, caused fetal growth restriction, increased placental weight, and increased maternal systolic blood pressure (by 16 mm Hg). Uterine arteries from aged dams displayed reduced constriction to phenylephrine (young: 14.3±0.94 mN/mm versus aged: 11.4±0.5 mN/mm, P =0.02) and potassium chloride (124 mmol/L; young: 21.8±1.27 mN/mm versus aged: 14.2±1.7 mN/mm; P =0.01). Methacholine-induced vasodilation was similar in uterine arteries from young and aged dams. However, mesenteric arteries from aged dams had a greater nitric oxide and a reduced endothelial-derived hyperpolarization contribution to methacholine-mediated vasodilation compared with young dams. Both uterine and mesenteric arteries from aged dams had greater active myogenic responses, with area under the curve increased by 228% and 151%, in aged uterine and mesenteric arteries, respectively. These results demonstrate that vascular function is altered at an advanced maternal age and provides further insights into the risks of poor pregnancy outcomes observed in women who delay pregnancy.

This study was undertaken to determine whether perinatal maternal resveratrol (Resv)—a phytoalexin known to confer cardiovascular protection—could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (−18 mm Hg; P =0.007), and nitric oxide synthase inhibition (with l -NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with l -NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide–independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (−28%; P <0.05), and this difference could be normalized by l -NG-nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats.

Preeclampsia is a leading cause of maternal and fetal morbidity/mortality; however, the pathophysiological mechanisms are unclear. Vascular endothelial dysfunction in preeclampsia has been partially attributed to changes in endothelin-1 (ET-1). Several enzymes, including matrix metalloproteinases (MMPs; particularly MMP-2), cleave the inactive precursor big ET-1 (bET-1) to active ET-1. Notably, expression levels of MMP-2 have been shown to be on the increase in women who subsequently develop preeclampsia. We hypothesized that the increased MMP-2 expression leads to increased bET-1 conversion, thereby increasing vasoconstriction in preeclampsia. A reduced uteroplacental perfusion pressure (RUPP) model of preeclampsia in the rat was used to assess mesenteric artery vascular function. Responses to bET-1 (3–310 nmol/L) and ET-1 (1–200 nmol/L) were studied in the presence or absence of inhibitors of enzymes known to cleave bET-1. Vascular contractility in response to bET-1 was greater in RUPP than Sham (P<0.001), whereas neither responses to ET-1 nor maximal contractility to high potassium salt solution (123.70 mmol/L) were different. MMP inhibition with GM6001 (30 μmol/L) significantly decreased responses to bET-1 in RUPP (P<0.001) but not Sham-operated rats. Interestingly, combined treatment with GM6001 and L-NG-nitroarginine methyl ester (100 μmol/L) revealed a NO modulation of MMPs that was reduced in RUPP. In summary, we found increased vascular contractility to bET-1 in the RUPP model of preeclampsia that was likely attributable to upstream enzymatic pathways. These data are consistent with a greater contribution of MMP to cleavage of bET-1 to ET-1 ex vivo in RUPP, suggesting that this enzyme may be partially responsible for increased bET-1–induced contractility.