Effect of nicotine on placental ischemia-induced complement activation and hypertension in the rat

Abstract

Preeclampsia is a pregnancy-specific condition manifested by new-onset maternal hypertension with systemic inflammation, including increased innate immune system complement activation. While exact pathophysiology is unknown, evidence suggests that inadequate spiral artery invasion and resulting utero-placental insufficiency is the initiating event. Cigarette smoking during pregnancy decreases the risk of preeclampsia. Nicotine, a major component of cigarettes, stimulates the efferent cholinergic anti-inflammatory pathway through peripherally expressed nicotinic acetylcholine receptors (nAChR) and is known to attenuate ischemia-reperfusion injury in kidney and liver. Prior studies indicated that complement activation was critical for placental ischemia-induced hypertension in a rat model. Thus, it was hypothesized here that nicotine was responsible for the protective effect of cigarette smoking in preeclampsia and would attenuate placental ischemia-induced systemic complement activation and hypertension. The Reduced Utero-placental Perfusion Pressure (RUPP) model in the pregnant rat was employed to induce placental ischemia, resulting in complement activation, fetal resorptions, and hypertension. On gestation day (GD)14, nicotine (1 mg/kg) or saline was administered via subcutaneous injection prior to RUPP surgery and daily through GD18. On GD19, placental ischemia significantly increased mean arterial pressure (MAP) in saline injected animals. However, the placental ischemia-induced increase in blood pressure was not evident in nicotine-treated animals and nicotine treatment significantly increased MAP variability. Circulating C3a was measured as an indicator of complement activation and increased C3a in RUPP compared to Sham persisted with nicotine treatment, as did fetal resorptions. These data suggested to us that nicotine may contribute to the decreased risk of preeclampsia with cigarette smoking, but this protective effect was confounded by additional effects of nicotine on the cardiovascular system.

Keywords: Preeclampsia; complement; gestational hypertension; hypertension; nicotine; placental ischemia; smoking.

Figure 1.

Nicotine effect on MAP and contractile response of mesenteric arteries following placental ischemia. RUPP or Sham animals were treated with nicotine or saline vehicle GD14–18 and MAP and contractile responses determined on GD19. (A) MAP increased in RUPP Vehicle (n= 7) compared to Sham Vehicle (n=7), but RUPP Vehicle was not significantly greater than RUPP animals treated with 1 mg nicotine/kg/day (RUPP Nicotine, n = 9). RUPP Nicotine was not significantly different from Sham Nicotine (n = 8) treated animals. *p < 0.05. (B) RUPP surgery significantly increased the active tension generated in response to 0.57 μM U46619 comparing RUPP Vehicle (n = 6) to Sham Vehicle (n = 6). In nicotine-treated animals, the contractile response to U46 was significantly higher in RUPP (n = 8) vs. Sham (n = 5). *p < 0.05.

Figure 2.

Nicotine does not alter the fraction of fetuses resorbed. In vehicle-treated animals, RUPP surgery (n = 7) increased pup resorptions compared to Sham (n = 7). This effect persisted with nicotine treatment in RUPP (n = 9) and Sham (n = 8). *p < 0.05.

Figure 3.

Nicotine does not affect the placental ischemia-induced increase in circulating C3a. C3a serum concentration is increased in RUPP Vehicle (n = 7) vs. Sham Vehicle (n = 7). Treatment with 1 mg nicotine/kg/day over a 5-day period did not attenuate the RUPP (n = 8) increase in C3a compared to Sham (n = 8). *p < 0.05.