Chronic Prenatal Hypoxia Down-Regulated BK Channel Β1 Subunits in Mesenteric Artery Smooth Muscle Cells of the Offspring

Abstract

Background/Aims: Chronic hypoxia in utero could impair vascular functions in the offspring, underlying mechanisms are unclear. This study investigated functional alteration in large-conductance Ca²⁺-activated K⁺ (BK) channels in offspring mesenteric arteries following prenatal hypoxia. Methods: Pregnant rats were exposed to normoxic control (21% O₂, Con) or hypoxic (10.5% O₂, Hy) conditions from gestational day 5 to 21, their 7-month-old adult male offspring were tested for blood pressure, vascular BK channel functions and expression using patch clamp and wire myograh technique, western blotting, and qRT-PCR. Results: Prenatal hypoxia increased pressor responses and vasoconstrictions to phenylephrine in the offspring. Whole-cell currents density of BK channels and amplitude of spontaneous transient outward currents (STOCs), not the frequency, were significantly reduced in Hy vascular myocytes. The sensitivity of BK channels to voltage, Ca²⁺, and tamoxifen were reduced in Hy myocytes, whereas the number of channels per patch and the single-channel conductance were unchanged. Prenatal hypoxia impaired NS1102- and tamoxifen-mediated relaxation in mesenteric arteries precontracted with phenylephrine in the presence of N^ω-nitro-L-arginine methyl ester. The mRNA and protein expression of BK channel β1, not the α-subunit, was decreased in Hy mesenteric arteries. Conclusions: Impaired BK channel β1-subunits in vascular smooth muscle cells contributed to vascular dysfunction in the offspring exposed to prenatal hypoxia.

Preeclampsia link to gestational hypoxia

“…1). Interestingly, hypoxia and oxidative stress suppress BK Ca channel activity expression, which may explain the maladaptive myogenic response of the uteroplacental circulation in response to chronic hypoxia 38,105,106 (Fig. 2).…”

Prenatal hypoxia inhibited propionate‐evoked BK channels of mesenteric artery smooth muscle cells in offspring

“…K E Y W O R D S large-conductance calcium-activated potassium channels, offspring, prenatal hypoxia, propionate | 3193 ZHANG et Al.demonstrated in middle cerebral arteries, 2 mesenteric arteries, 3-6 renal arteries 7,8 and femoral arteries. 9,10 More studies described increased blood pressure responses and greater vasoconstrictions of resistance arteries in the offspring exposed to prenatal hypoxia, [11][12][13] which were associated with altered vascular constrictor and dilator mechanisms. Among underlying factors are calcium and potassium channels, which play pivotal keys in contraction and hyper-polarization of vascular smooth muscle cells (VSMCs), 7,11,12,14 respectively.Nevertheless, the detailed molecular mechanisms through which hypoxia in utero affects vascular functions of foetuses and offspring have yet to be elucidated.Short-chain fatty acids (SCFAs) are gut microbial metabolites produced by fermentation of dietary fibres, mainly including acetate, propionate and butyrate.…”

Mechanisms linking exposure to preeclampsia in utero and the risk for cardiovascular disease

“…Progeny cardiac dysfunction is common to all of these models, although with some variation in phenotype and different sets of outcomes studied in each model. Hypertension at baseline and/or in response to stress or adrenaline has been reported in progeny of the RUPP rat, 10,41-45,52,57 hypoxic rat 47,48,58,59 and in males but not females in the sFlt1-transduced mice model of PE. 30,54 Interestingly, progeny of the L-NAME-treated rat are normotensive as young and mature adults.…”

“…In each of these models, progeny are lighter at birth but catch up in body weight to that of controls during or before adulthood. 37,[41][42][43][44][45][46][47][48][49][50][51] Development of obesity is variable, with obesity reported in adult female, but not male, RUPP rats with ageing, 52,53 but normal body and central fat abundance in adult progeny of sFlt1-transduced mice of both sexes. 54 Likewise, effects of in utero exposure to a preeclamptic phenotype on postnatal glucose tolerance are sex-and agedependent in the RUPP rat, 53,55 L-NAME-treated rat 56 and sFlt1-transduced mice 51 models of PE.…”

“…10,42,43,52,57 Similarly, in progeny of hypoxic rat dams, phenylephrine-induced vasoconstriction is greater, and both endothelium-dependent and endothelium-independent vasodilatation are reduced compared to control progeny. 36,47,48,61,62 Progeny heart structure and function are also impaired in several of these models. For example, cardiac and cardiomyocyte size are normal at 3 months of age in young male adults whose mothers were exposed to intermittent hypoxia from early pregnancy (10% O 2 for 3 h/day from GD7 to 21) 59 .…”