Published Online
on July 21, 2003

A more recent version of this article appeared on October 1, 2003

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Submitted on May 5, 2003
Revised on May 23, 2003

Reduced Endothelial Vascular Relaxation in Growth-Restricted Offspring of Pregnant Rats With Reduced Uterine Perfusion

Jason A. Payne; Barbara T. Alexander; and Raouf A. Khalil^*

From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss (J.A.P., B.T.A.); and from Research and Development, Department of Veterans Affairs Medical Center, West Roxbury, and the Department of Medicine, Harvard Medical School, Boston, Mass (R.A.K.).

^* To whom correspondence should be addressed. E-mail: raouf_khalil{at}hms.harvard.edu.

Abstract--Low birth weight as the result of placental insufficiency increases the risk of hypertension in young adults; however, the vascular mechanisms involved are unclear. We tested the hypothesis that intrauterine fetal growth restriction caused by placental insufficiency results in low-birth-weight offspring with impaired endothelium-dependent vascular relaxation, enhanced vasoconstriction, and hypertension. The body weight and arterial pressure were measured in young (4 weeks), adolescent (8 weeks), and adult (12 weeks) male offspring of normal pregnant rats and pregnant rats with reduced uteroplacental perfusion (intrauterine growth-restricted, IUGR), and aortic strips were isolated for measurement of isometric contraction. The body weight was lower whereas the arterial pressure was higher in IUGR than normal rats at 4 weeks (113±3 versus 98±2), 8 weeks (133±3 versus 121±6), and 12 weeks (144±4 versus 131±3 mm Hg). Phe (10^-5 mol/L) caused an increase in active stress that was greater in IUGR than in normal rats at 4 weeks (12.4 versus 7.8), 8 weeks (13.3 versus 8.4), and 12 weeks (14.6 versus 9.0x10⁴ N/m²). Removal of the endothelium enhanced Phe-induced stress in normal but not IUGR rats. In endothelium-intact strips, acetylcholine (ACh) caused relaxation of Phe contraction and induced nitrite/nitrate production that were smaller in IUGR than normal rats. L-NAME (10^-4 mol/L), which inhibits NO synthase, or ODQ (10^-5 mol/L), which inhibits cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe contraction in normal but not IUGR rats. Thus endothelium-dependent NO-mediated vascular relaxation is inhibited in IUGR offspring of pregnant rats with reduced uteroplacental perfusion, and this may explain the increased vascular constriction and arterial pressure in young adults with low birth weight.

Key words: arteries • endothelium • nitric oxide • muscle, smooth, vascular • vasculature

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