Preeclampsia (PE), new-onset hypertension during pregnancy alongside organ dysfunction, is a leading cause of morbidity and mortality for the mother and fetus.PE women have activated B cells that produce agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA).AT1-AA impairs cerebral blood flow (CBF) autoregulation during pregnancy.Although AT1-AA often remains elevated up to 8 years postpartum, AT1-AA's effect on CBF autoregulation postpartum is unknown.This study examined whether elevated AT1-AA during pregnancy impairs CBF autoregulation postpartum and if this was augmented by infusion of AT1-AA postpartum.AT1-AA was infused into 12-week-old timed-pregnant Sprague Dawley rats beginning on gestational day 14.Uterine artery resistance index (UARI) was measured on gestational day 18 as a measure of endothelial dysfunction associated with PE.Dams were allowed to deliver.One group was given a second infusion of AT1-AA (50% perinatal dose mimicking levels observed in postpartum PE women) at 9 weeks postpartum.After postpartum week 10, mean arterial pressure (MAP) was measured in conscious rats and CBF autoregulation was measured by laser Doppler flowmetry.AT1-AA during pregnancy increased UARI (P<0.05).AT1-AA during pregnancy did not affect MAP postpartum but did impair CBF autoregulation postpartum.Infusion of AT1-AA postpartum significantly elevated blood pressure (P<0.01)but did not further impair CBF autoregulation.This study demonstrates that circulating AT1-AA during pregnancy causes impairment of CBF autoregulation well into the postpartum period indicating that elevated AT1-AA leads to long-term cerebrovascular consequences.Targeting AT1-AA may prevent cerebrovascular effects associated with PE during pregnancy and postpartum.

Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with increased cerebral blood flow (CBF), impaired cognitive function, and memory loss. We have shown adoptive transfer of placental CD4+ T cells from PE women into athymic nude pregnant rats causes HTN and increased circulating factors associated with PE. COVID-19 (CV) during pregnancy is associated with increased diagnosis of PE. However, the role of CD4+ T cells stimulated in response to CV in contributing to the PE phenotype in patients with a Hx of CV during pregnancy is unknown. We hypothesize adoptive transfer of placental CD4+ T cells from patients with a CV History (Hx) during pregnancy with PE causes HTN, CBF alterations, and cognitive dysfunction in pregnant athymic nude recipient rats. Placental CD4+ T cells were isolated from normotensive (NP), PE, Hx of CV normotensive (CV Hx NT), and Hx of CV with PE (CV Hx+PE) at delivery. One million CD4+ T cells were injected i.p. into nude athymic rats on gestational day (GD) 12. A Barnes maze and the novel object recognition assays were used to assess cognitive function on GDs 15-19. Blood pressure (MAP) and CBF were measured by carotid catheter and laser Doppler flowmetry on GD19, respectively. A two-way ANOVA was used for statistical analysis. MAP increased in CV Hx+PE (111±4, n=4) and PE recipient rats (115±2 mmHg, n=5) compared to CV Hx NT (100±4, n=5) and NP (99±3 mmHg, n=4 p< 0.05). CV Hx+PE and PE exhibited greater latency with more errors in the Barnes maze compared to CV Hx NT and NP groups. Locomotor activity was decreased in CV Hx+PE (P< 0.05) compared to PE, CV Hx NT, and NP groups. CV Hx+PE and PE exhibited short term memory dysfunction compared to CV Hx NT and NP groups. PE and CV Hx+ PE had impaired autoregulation of CBF compared to CV Hx NT and NP rats. Our findings indicate that pregnant recipients of CD4+ T cells from PE with or without a Hx CV during pregnancy cause HTN, impaired CBF and cognitive dysfunction compared to recipients of NP or NT Hx COVID-19 CD4 + T cells.

Preeclampsia (PE), new-onset hypertension during pregnancy, is the leading cause of morbidity and mortality for the mother and the fetus. A leading cause of mortality during PE is cerebrovascular disease. Women with PE have activated B cells producing agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) which remain elevated in maternal circulation up to 8 years postpartum (PP). AT1-AA contributes to endothelial dysfunction in the kidney, placenta, and brain during pregnancy. We believe it plays a role in the increased incidents of cardiovascular and cerebrovascular disorders in PP PE women. We have shown at AT1-AA infusion into pregnant rats results in elevated mean arterial pressure (MAP), impaired cerebral blood flow (CBF) autoregulation, and reduced pup weight. However, the effects of perinatal AT1-AA and sustained AT1-AA PP on MAP and CBF hemodynamics in the PP period is unknown. We hypothesize that AT1-AA induced hypertension during pregnancy will cause maternal hypertension and impaired maternal CBF PP.To test this hypothesis, AT1-AA (1:40) was infused into pregnant Sprague Dawley rats on gestational day (GD) 14 via a mini-osmotic pump. On GD18, uterine artery resistance index (UARI) was measured by Doppler ultrasound. Dams were allowed to deliver and pup weights were recorded within 12 hours. PP dams were aged to 9 weeks after birth and one group of AT1-AA PP dams received a second infusion of AT1-AA (1:80), to mimic the levels of AT1-AA seen in PP PE women. At 10 weeks PP, maternal MAP was measured and at 12 weeks PP, CBF autoregulation was measured by laser Doppler flowmeter.At GD 18, UARI was elevated in AT1-AA infused rats (0.610±0.080, n=7, P<0.05) compared to NP rats (0.475±0.070, n=5). At PP week 10, MAP was elevated in AT1-AA + AT1-AA (1:80) PP (129±1 mmHg, n=5, P<0.01) compared to NP (120±2 mmHg, n=5) and AT1-AA (120±1 mmHg, n=6). CBF increased by 34±4% (P<0.05, n=8) in rats with AT1-AA during pregnancy and by 39±4% (P<0.05, n=8) in rats with AT1-AA during pregnancy and (1:80) PP in response to increased MAP from 100 to 140 mmHg, versus only 4±3% (n=8) in normal pregnant controls.In conclusion, AT1-AA during pregnancy causes sustained changes in CBF hemodynamics PP. Increased AT1-AA PP also causes elevated blood pressures in association with impaired CBF. These data indicate that perinatal and PP AT1-AA cause long-term cardiovascular and cerebrovascular consequences for PE women. Targeting AT1-AA may prevent cerebral vascular and neurological defects in PE, and alleviate some of the long-term impact postpartum. This study was supported in part by NIH grants HD067541 (BL), H13865 (RJR).and P20GM121334 (BL, LA) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Preeclampsia (PE), new-onset hypertension during pregnancy, is the leading cause of morbidity and mortality for the mother and is associated with multi-organ dysfunction including the brain. Women with PE have activated B cells producing agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) which remain elevated in maternal circulation up to 8 years postpartum (PP); therefore, we believe it to play a role in PE pathophysiology and the increased incidents of cardiovascular disorders PP. Although we have shown at AT1-AA infusion into pregnant rats results in elevated mean arterial pressure (MAP), impaired cerebral blood flow (CBF) autoregulation, and reduced pup weight, we don’t know the effects of AT1-AA on MAP and CBF hemodynamics in the PP period. We hypothesize that AT1-AA induced hypertension during pregnancy will cause maternal hypertension and impaired maternal CBF PP. To test this hypothesis, AT1-AA (1:40) was infused on gestational day (GD) 14 via a mini-osmotic pump. Dams were allowed to deliver; pup weights were recorded within 12 hours. PP dams were aged to 9 weeks after birth and one group of AT1-AA PP dams received a second infusion of AT1-AA (1:80), to mimic the levels of AT1-AA seen in PP PE women. At 10 weeks PP, maternal MAP was measured and at 12 weeks PP, CBF autoregulation was measured by laser Doppler flowmeter. At PP week 12, MAP was 118±3 mmHg in NP (n=4), 119±2 mmHg in AT1-AA (n=5), and 126±5 in AT1-AA + AT1-AA (1:80) PP (P<0.05, n=5). CBF increased by 43±8% (P<0.05, n=2) in rats with AT1-AA during pregnancy and by 37±9% (P<0.05, n=4) in rats with AT1-AA during pregnancy and (1:80) PP in response to increased MAP from 100 to 140 mmHg, versus only 6±2% (n=3) in normal pregnant controls. In conclusion, AT1-AA during pregnancy causes sustained changes in CBF hemodynamics PP. Sustained maternal AT1-AA PP also causes increased blood pressures long-term in association with impaired CBF. These data indicate that perinatal and PP AT1-AA cause long-term cardiovascular and cerebrovascular consequences for PE women.

Mutations in CYP4F2 (rs2108622) and CYP4A11 (rs1126742) that inhibit the production of 20-HETE have been linked to hypertension in human genetic studies. We confirmed that these same variants are associated with hypertension and cognitive dysfunction in 4,286 elderly subjects in the Atherosclerosis Risk in Communities Neurocognitive Study . These studies establish that mutations in CYP enzymes that reduce 20-HETE promote hypertension, but the mechanisms remain controversial since 20-HETE has both pro- and antihypertensive actions. To address this question, we identified a homologous genetic deficiency in the formation of 20-HETE in Dahl S (SS) rats and created SS.5 BN consomic and CYP4A transgenic SS rats to restore CYP4A expression and 20-HETE production, and CYP4A2 and CYP4A3 KO rats on the rescued SS.5 BN background. Mean arterial pressure (MAP), renal and cerebral blood flow, proteinuria, and renal injury were compared in SS versus SS.5 BN and CYP4A transgenic SS rats and in SS.5 BN versus CYP4A2 and CYP4A3 KO rats. MAP increased from 117±2 to 158±5 mmHg (n=34) in SS rats fed a high salt (HS) diet for 3 weeks. Proteinuria rose from 50±4 to 403±30 mg/day. MAP increased less, from 108 + 5 to 133 + 5 mmHg (n=7) in CYP4A1 transgenic SS rats and from 109 + 2 to 132 + 2 mmHg (n=23) in SS.5 BN rats. Proteinuria (141±15 and 169±11 mg/day), glomerular injury, and renal fibrosis were all significantly reduced in the CYP4A transgenic and SS.5 BN rats compared to SS rats. KO of CYP4A2 had no effect on MAP (134 + 2 mmHg, n=23) or proteinuria (248 + 23 mg/day) relative to SS.5 BN rats fed an HS diet for 3 weeks. In contrast, MAP and proteinuria were elevated to 148 + 3 mmHg and 350 + 23 mg/day in CYP4A3 KO rats (n=23). The myogenic response of renal and cerebral arteries and autoregulation of RBF and CBF were impaired in SS and CYP4A3 KO rats but were intact in CYP4A transgenic SS rats, SS.5 BN and CYP4A2 KO rats. These findings indicate that a deficiency in the formation of 20-HETE that impairs the myogenic response of renal and cerebral arteries, autoregulation of RBF and CBF, and increases glomerular capillary pressure, promotes the development of hypertension, proteinuria, and renal injury in genetically susceptible individuals and SS rats.

ABSTRACT:Septic shock is life-threatening organ dysfunction due to a dysregulated response to infection. It is a leading cause of death caused by the excessive release of cytokines and inflammatory mediators in response to bacterial endotoxins. It produces hypotension refractory to vasoconstrictors leading to tissue hypoperfusion and multiple organ failure. Despite intensive investigation, there still are no specific pharmacologic treatments. Current therapy relies on supportive care, including antibiotics, fluid resuscitation, corticosteroids, and pressor agents. This commentary summarizes little-known previous observations that inhibition of vascular 20-hydroxyeicosatetraenoic acid (20-HETE) by nitric oxide plays a key role in sepsis. It also highlights the new and exciting current report by Tunctan et al (2022) in this issue of Journal of Cardiovascular Pharmacology that administration of a 20-HETE mimetic can prevent lipopolysaccharide-induced vascular hyporeactivity, hypotension, and tachycardia in rats by activating the recently discovered GPR75/20-HETE receptor. Overall, these results provide a compelling case for initiating 20-HETE clinical trials to prevent hypotension, multiple organ failure, and death in septic shock.

Alzheimer’s Disease (AD) is an emerging global health care crisis. However, underlying mechanisms are not understood well enough to translate to precision medicine. There is increasing evidence suggesting that AD is associated with brain hypoperfusion. However, it is unclear whether amyloid‐beta (Aβ) accumulation is a cause or consequence of AD, and how it contributes to cerebral hypoperfusion. The present study examined if Aβ accumulation induces cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde (arteriole‐to‐capillary) and retrograde (capillary‐to‐arteriole) pathways in the TgF344‐AD rat model of Alzheimer's disease. We first confirmed that AD rats displayed hippocampal‐based cognitive dysfunction at 6 months of age using an eight‐arm water maze. We then found that AD rats exhibited impaired myogenic response (MR) of middle cerebral arteries (MCAs) and penetrating and parenchymal arterioles (PAs) two months earlier than the onset of cognitive deficits using a Living System pressure myograph. AD rats displayed poor surface and deep cortical cerebral blood flow (CBF) autoregulation recorded by laser Doppler flowmetry, and reduced functional hyperemic response induced by whisker stimulation. Moreover, cell contractile capabilities, detected by collagen gel based‐cell contraction kit, were reduced in Aβ‐treated cerebral VSMCs isolated from F344 rats, similar as seen in VSMCs isolated from AD rats. Furthermore, we found that the productions of reactive oxygen species (ROS) and mitochondrial superoxide in cerebral VSMCs isolated from AD rats were elevated using DHE staining and MitoSOX staining. Moreover, AD cells exhibited reduced mitochondrial respiration and ATP production detected by the Seahorse Cell Mito Stress Test kit. AD cerebral VSMCs also exhibited disrupted actin cytoskeleton and contractile units utilizing immunohistochemistry. Oxidative stress, mitochondrial dysfunction, and actin cytoskeleton disorganization are all factors that are associated with the reduced contractile capabilities of cerebral VSMCs mediated MR and CBF autoregulation. In other studies, we found that capillary endothelial cell‐derived inward rectifier potassium (Kir2.1) activity, which is responsible for retrograde CBF regulation, was reduced in the brain of AD rats using Western blot. PAs with capillaries isolated from AD rats dilated to a lesser degree than WT rats in response to moderately elevated extracellular K+ (10 mM) applied to capillaries. Inhibition of Kir2.1 channels with ML133 diminished the vasodilatory response to a greater extent in WT rats. These findings indicate that Aβ accumulation is associated with cerebral hypoperfusion in AD by affecting cerebral vascular function via both anterograde and retrograde pathways and provide novel insight into the vascular contribution to AD.

We recently reported that cerebral vascular dysfunction leads to impaired autoregulation of cerebral blood flow (CBF), neurovascular coupling (NVC), and blood-brain barrier (BBB) leakage. The present study examined if cerebral vascular dysfunction precedes cognitive impairment in the TgF344-AD (AD) rat model of Alzheimer's disease. In the present study, we confirmed that the AD rats develop learning and memory deficits beginning at 24-week of age using an eight-arm water maze. AD rats (n = 11) took a longer time to escape and displayed more errors than age-matched wildtype (WT) rats (n = 6). We also completed a longitudinal comparison of the myogenic response (MR) of the middle cerebral artery (MCA) and found that the MR was similar in AD and WT rats at 8- to 12-week of age when perfusion pressure was increased from 40 to 180 mmHg. However, the MR was significantly reduced in 16-week old AD rats (n = 6) as the inner diameter of the MCA only decreased by 8.2 ± 2.4% when perfusion pressure was increased from 40 to 180 mmHg compared with 14.5% ± 2.0% in age-matched WT rats (n = 6). The impaired MR of the MCA was exacerbated in AD rats with aging. Autoregulation of CBF AD rats (n = 4) in vivo was impaired in the surface and deep cortex at 24-week of age compared to age-matched WT rats (n = 4). Furthermore, we found the contractile capability of the cerebral vascular smooth muscle cells (VSMCs) isolated from AD rats (n = 4) was significantly reduced compared with WT rats (n = 4), detected by the reduction in size of 15.7 ± 0.9% vs. 25.4 ± 1.0% using a collagen gel-based assay kit. These results provide evidence that cerebral VSMC dysfunction, impaired MR, and autoregulation of CBF precede the development of memory and learning deficits in the TgF344-AD rat model. However, the underlying mechanisms for the loss of VSMCs contractility in this AD model overexpressing mutant human amyloid precursor protein ( APPsw ) and presenilin 1 ( PS1ΔE9 ) genes remain to be determined. Nevertheless, these results provide novel insight into the vascular contribution to AD.

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage. NEW & NOTEWORTHY This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.

20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactivating mutations in the CYP enzymes that produce 20-HETE are associated with hypertension and stroke in man. We previously revealed that inactivating variants of CYP4A/F enzymes are associated with dementia in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NS) population. 20-HETE is involved with sodium regulation in the kidney and is a powerful vasoconstrictor. It was recently discovered that CCL5 and 20-HETE share the same receptor, GPR75. We previously found that 20-HETE constricts and augments the myogenic response (MR) of the middle cerebral artery (MCA) and renal afferent arteriole. However, whether CCL5 has any effect on penetrating arterioles (PAs) and interacts with 20-HETE is unknown. We found that GPR75 is expressed in PAs and pericytes in the brain. CYP4A is also expressed in pericytes and is inversely proportional to levels of GPR75 in the brain. In the present study, we found that 20-HETE contributes to the basal myogenic tone of PAs in SD rats. Administration of HET0016, a 20-HETE synthesis inhibitor, dilated the PA by 34 ± 3% (n = 6) under 10 mmHg perfusion pressure. Administration of WIT003, a 20-HETE agonist, constricted the vessel by 23 ± 4% (n = 6) under the same perfusion pressure. We found that CCL5 also reduced PA diameter by 20 ± 4% (n = 7) in SD rats under 10 mmHg perfusion pressure. Moreover, we compared the response to CCL5 in SS rats that are 20-HETE deficient and SS.CYP4A1 transgenic rats in which 20-HETE production is restored. PAs isolated from SS rats treated with 0.1 nM CCL5 constricted by 9 ± 5% (n = 6) while those treated with 10 nM constricted by 12 ± 3% (n = 6). CCL5 had a greater response in PAs from the SS.CYP4A1 strain, and the diameter of the PAs constricted by 14 ± 2% (n = 5) and 24 ± 5% (n = 5) in response to 0.1 and 10 nM CCL5, respectively. These results demonstrate that CCL5 has a direct effect on PAs similar to 20-HETE that acts via the GPR75 receptor. However, further study is needed to determine how CCL5 and 20-HETE interact to promote vasoconstriction. These studies would help further understand the involvement of 20-HETE in disease and potentially identify novel drug targets.

We have previously identified an inactivating mutation of ADD3 in FHH rats which is associated with impaired myogenic reactivity of renal arterioles and podocyte function, and contributes to the development of CKD. We have found that SNPs in human ADD1 or ADD3 in the same region as Add3 in FHH rats are linked to reductions in brain volumes and impaired performance on cognitive tests in 4,286 elderly patients (67-90 years old) in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), but the mechanisms of these pathologies are unclear. The present study examined cerebral hemodynamics and cognitive function in FHH versus FHH.1BN and FHH. Add3 rats that express the WT Add3 gene. The myogenic responses of the middle cerebral artery (MCA) and parenchymal arterioles (PA) were impaired in FHH rats. MCA diameter decreased by 15-20% in FHH.1BN (n = 27) and FHH. Add3 (n = 10) transgenic rats, but increased by 9 ± 3% in FHH rats (n = 15) when perfusion pressure was increased from 40 to 160 mmHg. PA diameter increased by 3.16 ± 2.79% in FHH (n = 5) rats versus a 19 ± 3% and 13 ± 2% decrease FHH. Add3 (n = 4) and FHH.1BN (n = 6), respectively, when pressure was increased from 10 to 40 mmHg. Autoregulation of surface and deep cortical blood flow was impaired in FHH rats and rose by 48 ± 3% (n = 22) and 41 ± 3% (n = 12), respectively, versus 32 ± 3% (n = 7) and 16 ± 5% (n = 6) in FHH. Add3 rats when MAP was increased from 100 to 160 mmHg. By using a fluorescent microscope to examine 60 μm brain sections, it was revealed that the outer diameters of PAs were distended in FHH in comparison to FHH.1BN and FHH. Add3 transgenic rats when systemic pressure was increased to 160 mmHg. Blood brain barrier leakage was also greater in FHH rats than in FHH.1BN and FHH. Add3 rats after acute elevations in pressure. FHH (n=16) rats took 40- 50% longer to navigate an eight-arm water maze than FHH. Add3 (n=11) and FHH.1BN (n=7) rats. These results indicate that variants that alter Add3 function promote cognitive dysfunction in FHH rats by altering cerebral hemodynamics and may play a similar role in cognitive deficits in elderly patients in the ARIC-NCS study. This study suggests that blood pressure should be strictly controlled in hypertensive patients identified with ADD3 variants to prevent dementia.

Preeclampsia (PE) is characterized by the abrupt onset of high blood pressure, systemic inflammation, and widespread vascular dysfunction. Specifically, early onset PE is associated with attenuated trophoblast migration and improper spiral artery remodeling that leads to placental ischemia and release of inflammatory and anti‐angiogenic factors into the maternal circulation. A major risk factor for the development of preeclampsia is obesity; yet, the underlying mechanism that contributes to the increased risk of preeclampsia in obese patients is not clear. Circulating saturated fatty acids (SFAs) are elevated in obese and preeclamptic women and have been shown to stimulate inflammatory pathways by triggering toll‐like receptors (TLRs) and inflammatory responses. While SFAs are elevated in PE, it is unknown whether they contribute to the pathophysiology of preeclampsia. We hypothesized that elevated SFAs stimulate TLRs on trophoblast cells and attenuate trophoblast migration. To test this hypothesis, we cultured Bewo human trophoblasts with the SFAs palmitate (PAL), stearate (STE), or myristate (MYR) for 24 hours at concentrations mimicking SFA levels in preeclamptic (0.2 mM, 1.6:1 SFA:albumin molar ratio) or healthy pregnant (0.9:1 SFA:albumin) women. Trophoblasts were allowed to migrate for 4 hours before assessing migration. SFA exposure at 1.6:1 molar ratio to albumin significantly decreased trophoblast migration when compared to albumin vehicle controls set at 100% (PAL 69.6 ± 3.1%, STE 63.7 ± 2.6%, and MYR 65.4 ± 2.8%, p<0.01), and this decrease in migration was not observed when trophoblasts were exposed to SFA concentrations reported in healthy pregnant women (PAL 92.1 ± 2.4%, STE 111.8 ± 3.2%, and MYR 107.3 ± 3.3%). To investigate whether SFAs stimulated TLRs on Bewo cells, TLR‐2 and TLR‐4 were blocked for 24 hours prior to incubation with SFAs. Blockade of TLR‐4 on Bewo cells significantly restored trophoblast migration capacity when exposed to all SFAs (PAL 108.5 ± 6.3%, STE 108.4 ± 4.3%, and MYR 110.2 ± 3.0%, p<0.01). However, blockade of TLR‐2 only restored migration after exposure to PAL (106.1 ± 3.8%, p<0.01). Additionally, cytotoxicity and reactive oxygen species (ROS) generation assays were performed to determine if decreased trophoblast migration was due to cellular damage mechanisms. Exposure to 0.2 mM MYR significantly enhanced ROS production when compared to control ROS levels (Control MFI: 876.4 ± 102.8, MYR MFI: 1474 ± 129.8, p<0.05), but this increase in ROS generation did not result in enhanced cytotoxicity. PAL or STE exposure did not significantly alter ROS production or cytotoxicity in Bewo trophoblasts. Altogether, our data demonstrates that SFAs attenuate trophoblast migration through TLR signaling mechanisms. Further studies are ongoing to examine TLR‐driven phenotypic alterations in Bewo trophoblasts that result in decreased trophoblast migration. The major findings of this study reveal the impact of elevated SFAs on the pathophysiology of early onset preeclampsia. Support or Funding Information Funding: T32HL105324, P01HL051971, and P20GM104357. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .