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Pregnancy Increases Soluble and Particulate Guanylate Cyclases and Decreases the Clearance Receptor of Natriuretic Peptides in Ovine Uterine, But Not Systemic, Arteries¹

Department of Obstetrics and Gynecology, Perinatal Research Laboratories (H.I., I.M.B., R.R.M.), and Department of Meat/Animal Science (R.R.M.), University of Wisconsin, Madison, Wisconsin 53715; and the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (K.N.), Kyoto 606–01, Japan

Address all correspondence and requests for reprints to: Ronald R. Magness, Ph.D., Perinatal Research Laboratories, Department of Obstetrics and Gynecology, University of Wisconsin, 7E Meriter Hospital/Park 202 South Park Street, Madison, Wisconsin 53715. E-mail: rmagness{at}facstaff.wisc.edu

Pregnancy increases uterine blood flow by 30- to 50-fold and uterine production of cGMP by 38-fold. Moreover, cGMP causes potent vasodilatation. We hypothesized that pregnancy up-regulates soluble and particulate guanylate cyclases (sGC and pGC) in ovine uterine arteries. Activities of sGC and pGC were compared by measuring cGMP production (37 C; 10 min) by uterine arteries from nonpregnant (n = 5) and pregnant (n = 4, 120 ± 2 days’ gestation; term = 145 ± 3 days; mean ± SE) ewes after sodium nitroprusside (100 µM), atrial natriuretic peptide (1 µM), or C-type natriuretic peptide (CNP; 1 µM) treatment. The protein and/or messenger RNA expressions of sGC ß1-subunit, pGC-A, pGC-B, the clearance receptor of natriuretic peptide (CR), and CNP were investigated in uterine and systemic (renal and/or omental) arteries from nonpregnant (n = 29) and pregnant (n = 21; 125 ± 2 days’ gestation) ewes. The potencies of uterine arterial GC activities were sGC >> pGC-A > pGC-B. Activities as well as protein expression of sGC, pGC-A, and pGC-B in pregnant uterine arteries were increased 48–128% above those in nonpregnant controls concomitant with a 34% down-regulation of CR protein expression; systemic arterial protein expressions were unaltered. These changes in uterine arterial GC-B and CR were confirmed using RT-PCR. Immunohistochemical staining of CNP in uterine, but not systemic, arterial endothelium from pregnant ewes was much stronger than that from nonpregnant ewes. Thus, two distinct GC pathways are present in ovine uterine artery, and both may be specifically up-regulated during pregnancy and so contribute to the tremendous local increase in cGMP production during pregnancy.

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