Functional changes in the uterine artery precede the hypertensive phenotype in a transgenic model of hypertensive pregnancy

Abstract

The pregnant female human angiotensinogen (hAGN) transgenic rat mated with the male human renin (hREN) transgenic rat is a model of preeclampsia (TgA) with increased blood pressure, proteinuria, and placenta alterations of edema and necrosis at late gestation. We studied vascular responses and the role of COX-derived prostanoids in the uterine artery (UA) at early gestation in this model. TgA UA showed lower stretch response, similar smooth muscle ␣-actin content, and lower collagen content compared with Sprague-Dawley (SD) UA. Vasodilation to acetylcholine was similar in SD and TgA UA (64 Ϯ 8 vs. 75 Ϯ 6% of relaxation, P Ͼ 0.05), with an acetylcholine-induced contraction in TgA UA that was abolished by preincubation with indomethacin (78 Ϯ 6 vs. 83 Ϯ 11%, P Ͼ 0.05). No differences in the contraction to phenylephrine were observed (159 Ϯ 11 vs. 134 Ϯ 12 %KMAX, P Ͼ 0.05), although in TgA UA this response was greatly affected by preincubation with indomethacin (179 Ϯ 16 vs. 134 Ϯ 9 %KMAX, P Ͻ 0.05, pD2 5.92 Ϯ 0.08 vs. 5.85 Ϯ 0.03, P Ͻ 0.05). Endothelium-independent vasodilation was lower in TgA UA (92 Ϯ 2 vs. 74 Ϯ 5% preconstricted tone, P Ͻ 0.05), and preincubation with indomethacin restored the response to normal values (90 Ϯ 3 vs. 84 Ϯ 3%). Immunostaining showed similar signals for ␣-actin, COX-2, and eNOS between groups (P Ͼ 0.05). Plasma thromboxane levels were similar between groups. In summary, TgA UA displays functional alterations at early gestation before the preeclamptic phenotype is established. Inhibition of COX enzymes normalizes some of the functional defects in the TgA UA. An increased role for COX-derived prostanoids in this model of preeclampsia may contribute to the development of a hypertensive pregnancy. preeclampsia; vasodilation; vasoconstriction; cyclooxygenase-2; endothelial nitric oxide synthase PREECLAMPSIA IS A COMMON DISORDER OF PREGNANCY that manifests with hypertension and proteinuria in the last term of pregnancy. It is proposed that hypertensive disorders of pregnancy originate from defective trophoblast invasion and result in vascular endothelial dysfunction triggered by placental ischemia (7). An increased response to vasoconstrictor agonists is characteristic of pregnancies at risk of developing preeclampsia (13).The transgenic female rat containing the human angiotensinogen (hAGN) gene mated with the male transgenic rat containing human renin (hREN) is an established rodent model (TgA) that mimics many features of preeclampsia, including high blood pressure and proteinuria in the last third of gestation, characteristics that are absent in the reverse mating (4). At late gestation, TgA rats display increased circulating and uteroplacental levels of angiotensin II (Ang II), whereas in the reverse mating only uteroplacental Ang II is increased (16). Thus species-specific dependency of renin and angiotensinogen for rodent and human proteins and their localization in the placenta and the circulation form the basis of this model. Increased circulating levels of Ang II may derive from...

Prophylactic Effects of Polymethoxyflavone-Rich Orange Peel Oil on Nω-Nitro-L-Arginine-Induced Hypertensive Rats

“…NO produced by eNOS relaxes blood vessels, inhibits proliferation of vascular smooth muscle cells, inhibits platelet aggregation and maintains normal vascular tension and arterial blood pressure. However, in hypertension, atherosclerosis and other pathological conditions, the NO produced by eNOS cannot maintain the normal tension of blood vessels on its own; iNOS can activate and produce relatively large amounts of NO, so blood pressure does not increase malignancy [40,41]. In this study, OPO could also increase nNOS and eNOS expression levels and reduce iNOS expression in hypertensive rats.…”

The role of α2‐adrenergic receptors in hypertensive preeclampsia: A hypothesis

“…It is important to note, however, that NO still plays a role in the vasodilation of the placental vasculature. Indeed, endothelium‐independent vasodilation, expressed as the vasodilatory response to the NO donor SNP, although reduced, was still present in preeclamptic placental vessels . This indicated that it might be the smooth muscle portion of the NO‐dependent vasodilatory pathway that is altered in preeclamptic vessels.…”

“…NO is a principal vasodilator released by ECs and diffuses to the underlying VSMC layer triggering vasorelaxation . Because of its potency in mediating vasorelaxation, several studies aimed at understanding the role of NO in the isolated UA of PE animal models and in human placental vessels . However, these studies have revealed inconsistent results with controversy regarding the presence or absence of NO‐induced vasodilation in PE.…”

“…Indeed, previous studies suggested a role for NO‐independent mechanisms for uterine and placental vessels dilation. UA preparations showed residual ACh‐evoked dilation upon treatment with L‐NAME that was abrogated with K + channel inhibitors . Therefore, whether NO‐independent mechanisms are unaltered or play a compensatory role in PE may provide an exciting insight into the pathology of this disease.…”

“…Indeed, endotheliumindependent vasodilation, expressed as the vasodilatory response to the NO donor SNP, although reduced, was still present in preeclamptic placental vessels. 80,82 This indicated that it might be the smooth muscle portion of the NO-dependent vasodilatory Significantly, a study investigating the interaction between the NO and α 2 -AR-mediated endothelium-dependent vasorelaxation in mesenteric arterial segments from mice lacking eNOS demonstrated an inhibitory role of NO on the α 2 -AR-mediated relaxation and that cGMP may be involved in this mechanism. 45 Thus, it becomes prudent to examine this vasorelaxation in PE, a setting with weak production/response to NO.…”