Maternal Obesity Impairs Specific Regulatory Pathways in Human Myometrial Arteries1

Abstract

Obese women (body mass index ≥30 kg/m(2)) are at greater risk than normal weight women of pregnancy complications associated with maternal and infant morbidity, particularly the development of cardiovascular disease and metabolic disorders in later life; why this occurs is unknown. Nonpregnant, obese individuals exhibit systemic vascular endothelial dysfunction. We tested the hypothesis that obese pregnant women have altered myometrial arterial function compared to pregnant women of normal (18-24 kg/m(2)) and overweight (25-29 kg/m(2)) body mass index. Responses to vasoconstrictors, U46619 (thromboxane mimetic) and arginine vasopressin, and vasodilators, bradykinin and the nitric oxide donor sodium nitroprusside, were assessed by wire myography in myometrial arteries from normal weight (n = 18), overweight (n = 18), and obese (n = 20) women with uncomplicated pregnancies. Thromboxane-prostanoid receptor expression was assessed using immunostaining in myometrial arteries of normal weight and obese women. Vasoconstriction and vasodilatation were impaired in myometrial arteries from obese women with otherwise uncomplicated pregnancies. Disparate agonist responses suggest that vascular function in obese women is not globally dysregulated but may be specific to thromboxane and nitric oxide pathways. Because obesity rates are escalating, it is important to identify the mechanisms underlying impaired vascular function and establish why some obese women compensate for vascular dysfunction and some do not. Future studies are needed to determine whether central adiposity results in an altered endocrine milieu that may promote vascular dysfunction by altering the function of perivascular adipose tissue.

Human supraphysiological gestational weight gain and fetoplacental vascular dysfunction

“…6 However, intrauterine early-life development in an environment of maternal obesity or spGWG increases the risk of cardiovascular disease 7 and adverse neonatal outcome (v.g., preterm delivery and umbilical cord arterial blood pH <7.1). 5,8 Even when women that were obese before pregnancy show endothelial dysfunction 9 , and spGWG associates with increased adiposity at birth 10 and with long-term implications on offspring cardiometabolic risk factors at young adult age 5 it is unknown whether spGWG affect the human fetoplacental vasculature. 5,6,[11][12][13] The human placenta lacks innervation, 14 thus local release of vasoactive molecules from the endothelium such as nitric oxide (NO) or adenosine, or systemic circulating factors such as insulin and adenosine, play key roles to maintain fetoplacental vascular function.…”

Exposure to omentum adipose tissue conditioned medium from obese pregnant women promotes myometrial artery dysfunction

“…Between the two conditioned medium conditions, OB medium versus NW medium exposure increased U46619‐induced vasoconstriction and reduced vasodilation to BK in MAs collected from NW women. Using arteries from NW women excluded the potential complicating effects of maternal obesity on vascular reactivity and offered us a model to try and mimic the responses previously observed in MAs from OB women …”

“…MAs (377 ± 95 μm diameter, 1–2 mm length) were carefully dissected, mounted on a Danish Myotechnology M610 wire myograph, normalized to an internal diameter of 0.9 of L 13.3kPa (luminal pressure ≈ 45 mmHg) and left to equilibrate (37°C, gassed with air/5% CO 2 ) in physiological salt solution (PSS; 119 mM NaCl, 25 mM NaHCO 3 , 4.69 mM KCl, 2.4 mM MgSO 4 , 1.6 mM CaCl 2 , 1.18 mM KH 2 PO 4 , 6.05 mM glucose, 0.034 mM EDTA; pH 7.4), as previously described . Vessel contractility was assessed using a high potassium solution (KPSS; 11 mM NaCl, 25 mM NaHCO 3 , 120 mM KCl, 2.4 mM MgSO 4 , 1.6 mM CaCl 2 , 1.18 mM KH 2 PO 4 , 6.05 mM glucose, 0.034 mM EDTA; pH 7.4) . MAs were exposed to maximal concentrations of thromboxane A 2 mimetic, U46619 (10 −5.7 M) and bradykinin (BK; 10 −5 M), an endothelium dependent vasodilation agonist to assess endothelium function.…”

“…Omental adipose tissue was collected in tissue collection buffer (154 mM NaCl, 5.4 mM KCl, 1.2 mM MgSO 4 , 1.6 mM CaCl 2 , 10 mM MOPS and 5.5 mM glucose; pH 7.4). 9 Fragments of tissue were dissected, washed in sterile phosphate buffered solution (10 tablets in 1 L distilled water, equivalent to 137 mM NaCl, 3 mM KCl, 8 mM Na 2 HPO 4 , 1.5 mM KH 2 PO 4 , pH 7.3) and sterile culture medium (containing Medium 199; 10% fetal calf serum; 1% L-Glutamine-Penicillin-Streptomycin solution [equivalent to 0.2 mM glutamine, 100 IU/mL penicillin, 100 μg/mL streptomycin sulfate]; and 0.25 μg/mL Amphotericin B). Using a similar method to that described previously in placental tissue, 19 omental adipose tissue explants were cultured on individual Costar Netwell supports (15 mm, 74 μm mesh) for 48 h at 37 C, 20% O 2 , 5% CO 2 .…”

“…8 Our previous studies demonstrate that, in OB pregnant women, myometrial artery (MA) function is impaired compared to MAs in normal weight women. 9 Furthermore, this was not a global dysregulation in MA function but appeared specific to the thromboxane and nitric oxide (NO) regulatory pathways. The mechanisms underpinning impaired contraction and vasodilation in OB pregnant women remain unclear.…”