American Journal of Physiology-heart and Circulatory Physiology, Oct 1, 2018
During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and gro... more During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and growth to maintain sufficient uteroplacental perfusion. Although we and others have shown that nitric oxide (NO) is a key mediator of these processes, the mechanisms that augment uterine artery NO signaling during gestation have not been identified. We hypothesized that Piezo1, a recently discovered cation channel, may be involved in the process of shear stress mechanotransduction, as other studies have shown that it is both mechanosensitive and linked to NO production. Surprisingly, there are no studies on Piezo1 in the uterine circulation. Our aims in the present study were to determine whether this novel channel is 1) present in uterine arteries, 2) regulated by gestation, 3) functionally relevant (able to elicit rises in intracellular Ca 2ϩ concentration and vasodilation), and 4) linked to NO. Immunohistochemistry confirmed that Piezo1 is present in uterine arteries, primarily but not exclusively in endothelial cells. Western blot analysis showed that its protein expression was elevated during gestation. In pressurized main uterine arteries, pharmacological activation of Piezo1 by Yoda1 produced near maximal vasodilation and was associated with significant increases in intracellular Ca 2ϩ concentration in endothelial cell sheets. Shear stress induced by intraluminal flow produced reversible vasodilations that were inhibited Ͼ50% by GsMTx-4, a Piezo1 inhibitor, and by N -nitro-L-arginine methyl ester/ N -nitro-L-arginine, inhibitors of NO synthase. These findings are the first to implicate a functional role for Piezo1 in the uterine circulation as a mechanosensor of endothelial shear stress. Moreover, our data demonstrate that Piezo1 activation leads to vasodilation via NO and indicate that its molecular expression is upregulated during pregnancy. NEW & NOTEWORTHY This is the first study to highlight Piezo1 in the uterine circulation. As a potentially important endothelial mechanosensor of shear stress, Piezo1 may be linked to mechanisms that support increased uteroplacental perfusion during pregnancy.
Mechanotransduction by vascular smooth muscle (VSM) is defined as a cellular response (contractio... more Mechanotransduction by vascular smooth muscle (VSM) is defined as a cellular response (contraction, secretion, growth, division) to transmural pressure or stretch. This review includes an overview of the physical forces VSM cells experience in vivo, consideration of experimental techniques used to study VSM mechanotransduction, and a discussion of the scientific literature pertinent to the individual cellular components that have been implicated in the transduction of physical forces. These include: the extracellular matrix, integrins, ion channels, the sarcoplasmic reticulum, second messenger systems, contractile proteins, and the cytoskeleton.
This is an open access article under the terms of the Creat ive Commo ns Attri bution License, wh... more This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Access to full text and tables of contents, including tentative ones for forthcoming issues: www.... more Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/jvr_issues 108 Antioxidants Reverse Age-Related Collateral Growth Impairment
blood flow a ml/min; total 700 ml/min, w the remaining estimate was In experime relative chang th... more blood flow a ml/min; total 700 ml/min, w the remaining estimate was In experime relative chang those of huma ing from 10t 10, 15, 26, 37, Since bloo unchanged du changes are decrease in ut plished by s mechanisms, enlargement o ing the veins), tion), and the standpoint, in combination o put and an exp teristic of gesta In humans in UPBF is gra which has a 22 blood flow are the last “trimes augmented flo in sheep (112) is a progressiv directed to the Kauer in the ra was placental 22), the value been made in Absolute bl in proportion blood flow (m excluding the somewhat (6, 37) during pre
Although pregnancy has long-lasting consequences for maternal vascular health, little is known ab... more Although pregnancy has long-lasting consequences for maternal vascular health, little is known about vascular changes postpartum (PP). Focusing on the uterine circulation, which undergoes unique structural and functional adaptation during gestation, we hypothesized that most pregnancy-induced changes would return to baseline PP, with minimal hysteresis. Large (main; MUA) and small (segmental; SUA) uterine arteries from adult Sprague Dawley rats ( n = 42) were evaluated 1 and 4 weeks PP (1PP, 4PP) and compared with those of late-pregnant (LP, day 21) and age-matched non-pregnant (NP) animals. Some comparisons were extended to mesenteric arteries to evaluate differences between reproductive and systemic vessels. Pregnancy-induced axial elongation regressed > 80% 1PP in MUAs and SUAs, although some minimal hysteresis remained 4PP. Circumferential growth was slower to regress, with no reductions in lumen diameter or media thickness 1PP; values returned to (MUA) or approached (SUA) NP values by 4PP. Changes in vascular smooth muscle cell cross-sectional area—a measure of hypertrophy—paralleled those in lumen diameter. Mesenteric and uterine artery compliance diverged during gestation, and continued to do so PP. Decreased MUA compliance 4PP was supported by an increased collagen:elastin ratio. Adrenergic sensitivity increased in uterine, and decreased in mesenteric arteries during pregnancy, and returned to NP values 4PP in both types of vessels. MUA α-1 adrenoceptor expression tracked along with sensitivity. Thus, postpartum adaptation varies by both parameter and vessel type. While many parameters regressed postpartum, alterations in compliance did not, suggesting that matrix changes may have long-term consequences for maternal vascular function and health.
Introduction: Reduced concentrations of placental protein 13 (PP13) during the first trimester of... more Introduction: Reduced concentrations of placental protein 13 (PP13) during the first trimester of human pregnancy are associated with elevated risk for the subsequent development of preeclampsia, which is one of the deadliest obstetrical complications of pregnancy. Previous studies by our group have shown that PP13 lowers blood pressure in pregnant rats, increases the size and weight of pups and placentas, and induces vasodilation of resistance arteries through endothelial signaling pathways involving endothelial nitric oxid synthase and prostaglandin. Methods: In the present study, the effect of PP13 was investigated in nonpregnant female Sprague Dawley rats (n=27). Osmotic pumps were surgically implanted subcutaneously that released a constant dose of PP13 or saline over 7 days. Most animals were sacrificed 6 days after the end of PP13 release (on day 13), while some were sacrificed immediately at the end of day 7 (the last PP13 release day), to compare the short-and long-term impact of PP13 on vessels' growth and size. Results: The uterine vessels were significantly expanded in the group exposed to recombinant PP13 (rPP13) compared to the control (saline) group. Both veins and arteries were significantly expanded by rPP13 with a more pronounced effect after 13 days compared to the corresponding vessels after 7 days. Furthermore, the long-term effect of treatment by rPP13 was more pronounced in the veins compared to the corresponding arteries. The effect of a PP13 variant with a histidine-tag (His-PP13) remained the same between 7 and 13 days. Conclusion: In conclusion, PP13 might play a key role in the expansive remodeling of the uterine vessels, reflecting what would happen if the rat was pregnant, preparing the uterine vasculature for the increase in uteroplacental blood flow, which is necessary for normal pregnancy. We suggest that PP13 could act by NO signaling pathways, a hypothesis that requires future study.
Background/Aims: Ten-eleven translocation 2 (Tet2), a DNA demethylase enzyme, has been identified... more Background/Aims: Ten-eleven translocation 2 (Tet2), a DNA demethylase enzyme, has been identified as a master epigenetic regulator of vascular smooth muscle cell plasticity. We hypothesized that pregnancy will induce significant adaptive changes in aortic biomechanics that correlate with the Tet family gene expression. Methods: Abdominal aortas from pregnant and nonpregnant mice were dissected and cannulated. Intraluminal pressure was adjusted using a pressure-servo system while using a video dimension analyzer to measure the lumen diameter. Quantitative polymerase chain reaction and immunoblot was used to analyze the expression of Tet genes. Global genomic methylation was assessed with the luminometric methylation assay. Results: Compared to the nonpregnant (NP, 706 ± 8 µm) control group, the aortic luminal diameter was significantly increased in both E18.5 (836 ± 14 µm) and PP30 (889 ± 16 µm) mice. Distensibility was reduced in E18.5 (90 ± 4%) mice and returned to NP values (108 ± 2%) in PP30 (108 ± 3%) mice. Tet2 transcription decreased at the beginning of pregnancy and subsequently increased in late gestation, inversely corresponding to changes in global methylation. Conclusion: Physiologic changes in the aorta were accompanied by changes in gene expression and genomic methylation, suggesting an epigenetic component to maternal vascular remodeling during pregnancy.
Placental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects... more Placental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects on isolated uterine arteries from nonpregnant and mid-pregnant rats. Vessels were isolated, cannulated, and pressurized to 50 mmHg within an arteriograph, preconstricted and exposed to increasing PP13 concentrations (10 −13-10 −8 M). PP13 elicited 38-50% arterial vasodilation with half-maximum response (EC 50) = 1 pM. The relaxation was mediated by activating the endothelialsignaling pathways of prostaglandin and nitric oxide (NO). Accordingly, these results encourage evaluation of PP13 as a possible therapy for gestational diseases characterized by insufficient uteroplacental blood flow and/or maternal hypertension.
Purpose of Review The goal of this review is to present the newest insights into what we view as ... more Purpose of Review The goal of this review is to present the newest insights into what we view as a central failure of cardiovascular adaptation in preeclampsia (PE) by focusing on one clinically significant manifestation of maternal endothelial dysfunction: nitric oxide signaling. The etiology, symptoms, and current theories of the PE syndrome are described first, followed by a review of the available evidence, and underlying causes of reduced endothelial nitric oxide (NO) signaling in PE. Recent Findings PE maladaptations include, but are not limited to, altered physiological stimulatory inputs (e.g., estrogen; VEGF/PlGF; shear stress) and substrates (L-Arg; ADMA), augmented placental secretion of anti-angiogenic and inflammatory factors such as sFlt-1 and Eng, changes in eNOS (polymorphisms, expression), and reduced bioavailability of NO secondary to oxidative stress. Summary PE is a complex obstetrical syndrome that is associated with maternal vascular dysfunction. Diminished peripheral endothelial vasodilator influence in general, and of NO signaling specifically, are key in driving disease progression and severity.
Background The regulation of vascular tone in the uterine circulation is a key determinant of app... more Background The regulation of vascular tone in the uterine circulation is a key determinant of appropriate uteroplacental blood perfusion and successful pregnancy outcome. Estrogens, which increase in the maternal circulation throughout pregnancy, can exert acute vasodilatory actions. Recently a third estrogen receptor named GPER (G protein-coupled estrogen receptor) was identified and, although several studies have shown vasodilatory effects in several vascular beds, nothing is known about its role in the uterine vasculature.
and/or altered physical forces secondary to adaptive changes in arterial diameter. These differen... more and/or altered physical forces secondary to adaptive changes in arterial diameter. These differences implicate pregnancy-specific pathways in the development and inhibition of myogenic tone, and point to potentially opposing roles of NO and hypertension.
Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of ... more Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of neurofilaments are seen in several neurodegenerative diseases, and this suggests that neurofilament transport is defective. Excitotoxic mechanisms involving glutamate are believed to be part of the pathogenic process in some neurodegenerative diseases, but there is currently little evidence to link glutamate with neurofilament transport. We have used a novel technique involving transfection of the green fluorescent proteintagged neurofilament middle chain to measure neurofilament transport in cultured neurons. Treatment of the cells with glutamate induces a slowing of neurofilament transport. Phosphorylation of the side-arm domains of neurofilaments has been associated with a slowing of neurofilament transport, and we show that glutamate causes increased phosphorylation of these domains in cell bodies. We also show that glutamate activates members of the mitogen-activated protein kinase family, and that these kinases will phosphorylate neurofilament side-arm domains. These results provide a molecular framework to link glutamate excitotoxicity with neurofilament accumulation seen in some neurodegenerative diseases.
To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling duri... more To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling during pregnancy, mice were injected with anti-FLT1 neutralizing antibody (Ab) beginning on Gestational Day 8 or 12 and every other day thereafter until Day 18; vehicle-only injected mice served as controls. Uterine artery blood flow was measured with ultrasound on Days 13 and 18, and morphometric measurements of the uterine arcade were carried out on Day 19 to provide a measure of gestational vascular remodeling; reproductive performance was evaluated by determining litter size, resorption rates, and pup and placental weights. Ab injections beginning on Day 8 or Day 12 resulted in significant reductions of uterine artery peak systolic and diastolic flows at Days 13 and 18. In addition, normal reproductive function was compromised, as evidenced by a significant reduction in average number of viable pups along with enhanced resorption rates. Reproductive performance was also significantly compromised in this group, although less severely. There was no evidence of a reduction in main uterine artery diameters, though arterial distensibility was reduced, and the diameter of the main uterine vein was significantly smaller in the Ab-injected mice. Significant reductions in main uterine artery and segmental artery length were also noted. Placental and pup weights were similar in all the groups. FLT1 inhibition during murine pregnancy impaired blood flow to the fetalplacental unit, compromised several indices of vascular remodeling, reduced fecundity, and increased fetal reabsorptions. The effects of FLT1 inhibition are most pronounced when targeted during early pregnancy.
Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery ou... more Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery outward circumferential remodeling during pregnancy. Although the underlying mechanisms are not known, they likely involve matrix metalloproteinases (MMPs). The goal of this study was to examine the linkage among NO inhibition, expansive remodeling, and MMP expression within the uterine vascular wall. Adult female rats were treated with NG-nitro-l-arginine methyl ester [l-NAME (LPLN)] beginning on day 10 of pregnancy and until death at day 20 and compared with age-matched controls [late pregnant (LP)]. Mean arterial pressure of LPLN rats was significantly higher than controls. LPLN fetal and placental weights were significantly reduced compared with controls. Main uterine arteries (mUA) were collected to determine dimensional properties (lumen area and wall thickness), collagen and elastin content, and levels of endothelial nitric oxide synthase (eNOS) and MMP expression. Circumferential r...
Increased pressure-induced (myogenic) tone in small uteroplacental arteries from late pregnant (L... more Increased pressure-induced (myogenic) tone in small uteroplacental arteries from late pregnant (LP) rats has been previously observed. In this study, we hypothesized that this response may result from a diminished activity of vascular smooth muscle cell (SMC) voltage-gated delayed-rectifier K+ (Kv) channels, leading to membrane depolarization, augmented Ca2+ influx, and vasoconstriction (tone). Elevation of intraluminal pressure from 10 to 60 and 100 mmHg resulted in a marked, diltiazem-sensitive rise in SMC cytosolic Ca2+ concentration ([Ca2+]i) associated with a vasoconstriction of uteroplacental arteries of LP rats. In contrast, these changes were significantly diminished in uterine arteries from nonpregnant (NP) rats. Gestational augmentation of pressure-induced Ca2+ influx through L-type Ca2+ channels was associated with an enhanced SMC depolarization, the appearance of electrical and [Ca2+]i oscillatory activities, and vasomotion. Exposure of vessels from NP animals to 4-amino...
American Journal of Obstetrics and Gynecology, 2002
OBJECTIVE: This study characterized the cellular remodeling that contributes to uterine venous gr... more OBJECTIVE: This study characterized the cellular remodeling that contributes to uterine venous growth during gestation and evaluated the effect of pregnancy on the mechanical properties of the uterine vein. STUDY DESIGN: Diameter and distensibility were calculated in pressurized uterine veins from virgin and pregnant (19-20 days of gestation) rats; the rates of cellular division (endothelial, vascular smooth muscle) were quantified with an intraperitoneal bromodeoxyuridine injection and immunohistochemistry. Elastin content, adrenergic nerve density, and wall thickness were determined in fixed uterine veins and quantified with an imaging program. RESULTS: There was a statistically significant increase in the diameter and mitotic indices (endothelial, vascular smooth muscle) in uterine veins from late pregnant versus nonpregnant animals. Adrenergic nerve density was diminished significantly during gestation. Venous distensibility increased during pregnancy, with an associated reduction in elastin content. CONCLUSION: Pregnancy results in coordinated and multifaceted structural remodeling of uterine veins with subsequent changes in caliber, mechanical properties, rates of cellular division, adrenergic innervation, and matrix composition.
American Journal of Physiology-heart and Circulatory Physiology, Oct 1, 2018
During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and gro... more During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and growth to maintain sufficient uteroplacental perfusion. Although we and others have shown that nitric oxide (NO) is a key mediator of these processes, the mechanisms that augment uterine artery NO signaling during gestation have not been identified. We hypothesized that Piezo1, a recently discovered cation channel, may be involved in the process of shear stress mechanotransduction, as other studies have shown that it is both mechanosensitive and linked to NO production. Surprisingly, there are no studies on Piezo1 in the uterine circulation. Our aims in the present study were to determine whether this novel channel is 1) present in uterine arteries, 2) regulated by gestation, 3) functionally relevant (able to elicit rises in intracellular Ca 2ϩ concentration and vasodilation), and 4) linked to NO. Immunohistochemistry confirmed that Piezo1 is present in uterine arteries, primarily but not exclusively in endothelial cells. Western blot analysis showed that its protein expression was elevated during gestation. In pressurized main uterine arteries, pharmacological activation of Piezo1 by Yoda1 produced near maximal vasodilation and was associated with significant increases in intracellular Ca 2ϩ concentration in endothelial cell sheets. Shear stress induced by intraluminal flow produced reversible vasodilations that were inhibited Ͼ50% by GsMTx-4, a Piezo1 inhibitor, and by N -nitro-L-arginine methyl ester/ N -nitro-L-arginine, inhibitors of NO synthase. These findings are the first to implicate a functional role for Piezo1 in the uterine circulation as a mechanosensor of endothelial shear stress. Moreover, our data demonstrate that Piezo1 activation leads to vasodilation via NO and indicate that its molecular expression is upregulated during pregnancy. NEW & NOTEWORTHY This is the first study to highlight Piezo1 in the uterine circulation. As a potentially important endothelial mechanosensor of shear stress, Piezo1 may be linked to mechanisms that support increased uteroplacental perfusion during pregnancy.
Mechanotransduction by vascular smooth muscle (VSM) is defined as a cellular response (contractio... more Mechanotransduction by vascular smooth muscle (VSM) is defined as a cellular response (contraction, secretion, growth, division) to transmural pressure or stretch. This review includes an overview of the physical forces VSM cells experience in vivo, consideration of experimental techniques used to study VSM mechanotransduction, and a discussion of the scientific literature pertinent to the individual cellular components that have been implicated in the transduction of physical forces. These include: the extracellular matrix, integrins, ion channels, the sarcoplasmic reticulum, second messenger systems, contractile proteins, and the cytoskeleton.
This is an open access article under the terms of the Creat ive Commo ns Attri bution License, wh... more This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Access to full text and tables of contents, including tentative ones for forthcoming issues: www.... more Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/jvr_issues 108 Antioxidants Reverse Age-Related Collateral Growth Impairment
blood flow a ml/min; total 700 ml/min, w the remaining estimate was In experime relative chang th... more blood flow a ml/min; total 700 ml/min, w the remaining estimate was In experime relative chang those of huma ing from 10t 10, 15, 26, 37, Since bloo unchanged du changes are decrease in ut plished by s mechanisms, enlargement o ing the veins), tion), and the standpoint, in combination o put and an exp teristic of gesta In humans in UPBF is gra which has a 22 blood flow are the last “trimes augmented flo in sheep (112) is a progressiv directed to the Kauer in the ra was placental 22), the value been made in Absolute bl in proportion blood flow (m excluding the somewhat (6, 37) during pre
Although pregnancy has long-lasting consequences for maternal vascular health, little is known ab... more Although pregnancy has long-lasting consequences for maternal vascular health, little is known about vascular changes postpartum (PP). Focusing on the uterine circulation, which undergoes unique structural and functional adaptation during gestation, we hypothesized that most pregnancy-induced changes would return to baseline PP, with minimal hysteresis. Large (main; MUA) and small (segmental; SUA) uterine arteries from adult Sprague Dawley rats ( n = 42) were evaluated 1 and 4 weeks PP (1PP, 4PP) and compared with those of late-pregnant (LP, day 21) and age-matched non-pregnant (NP) animals. Some comparisons were extended to mesenteric arteries to evaluate differences between reproductive and systemic vessels. Pregnancy-induced axial elongation regressed > 80% 1PP in MUAs and SUAs, although some minimal hysteresis remained 4PP. Circumferential growth was slower to regress, with no reductions in lumen diameter or media thickness 1PP; values returned to (MUA) or approached (SUA) NP values by 4PP. Changes in vascular smooth muscle cell cross-sectional area—a measure of hypertrophy—paralleled those in lumen diameter. Mesenteric and uterine artery compliance diverged during gestation, and continued to do so PP. Decreased MUA compliance 4PP was supported by an increased collagen:elastin ratio. Adrenergic sensitivity increased in uterine, and decreased in mesenteric arteries during pregnancy, and returned to NP values 4PP in both types of vessels. MUA α-1 adrenoceptor expression tracked along with sensitivity. Thus, postpartum adaptation varies by both parameter and vessel type. While many parameters regressed postpartum, alterations in compliance did not, suggesting that matrix changes may have long-term consequences for maternal vascular function and health.
Introduction: Reduced concentrations of placental protein 13 (PP13) during the first trimester of... more Introduction: Reduced concentrations of placental protein 13 (PP13) during the first trimester of human pregnancy are associated with elevated risk for the subsequent development of preeclampsia, which is one of the deadliest obstetrical complications of pregnancy. Previous studies by our group have shown that PP13 lowers blood pressure in pregnant rats, increases the size and weight of pups and placentas, and induces vasodilation of resistance arteries through endothelial signaling pathways involving endothelial nitric oxid synthase and prostaglandin. Methods: In the present study, the effect of PP13 was investigated in nonpregnant female Sprague Dawley rats (n=27). Osmotic pumps were surgically implanted subcutaneously that released a constant dose of PP13 or saline over 7 days. Most animals were sacrificed 6 days after the end of PP13 release (on day 13), while some were sacrificed immediately at the end of day 7 (the last PP13 release day), to compare the short-and long-term impact of PP13 on vessels' growth and size. Results: The uterine vessels were significantly expanded in the group exposed to recombinant PP13 (rPP13) compared to the control (saline) group. Both veins and arteries were significantly expanded by rPP13 with a more pronounced effect after 13 days compared to the corresponding vessels after 7 days. Furthermore, the long-term effect of treatment by rPP13 was more pronounced in the veins compared to the corresponding arteries. The effect of a PP13 variant with a histidine-tag (His-PP13) remained the same between 7 and 13 days. Conclusion: In conclusion, PP13 might play a key role in the expansive remodeling of the uterine vessels, reflecting what would happen if the rat was pregnant, preparing the uterine vasculature for the increase in uteroplacental blood flow, which is necessary for normal pregnancy. We suggest that PP13 could act by NO signaling pathways, a hypothesis that requires future study.
Background/Aims: Ten-eleven translocation 2 (Tet2), a DNA demethylase enzyme, has been identified... more Background/Aims: Ten-eleven translocation 2 (Tet2), a DNA demethylase enzyme, has been identified as a master epigenetic regulator of vascular smooth muscle cell plasticity. We hypothesized that pregnancy will induce significant adaptive changes in aortic biomechanics that correlate with the Tet family gene expression. Methods: Abdominal aortas from pregnant and nonpregnant mice were dissected and cannulated. Intraluminal pressure was adjusted using a pressure-servo system while using a video dimension analyzer to measure the lumen diameter. Quantitative polymerase chain reaction and immunoblot was used to analyze the expression of Tet genes. Global genomic methylation was assessed with the luminometric methylation assay. Results: Compared to the nonpregnant (NP, 706 ± 8 µm) control group, the aortic luminal diameter was significantly increased in both E18.5 (836 ± 14 µm) and PP30 (889 ± 16 µm) mice. Distensibility was reduced in E18.5 (90 ± 4%) mice and returned to NP values (108 ± 2%) in PP30 (108 ± 3%) mice. Tet2 transcription decreased at the beginning of pregnancy and subsequently increased in late gestation, inversely corresponding to changes in global methylation. Conclusion: Physiologic changes in the aorta were accompanied by changes in gene expression and genomic methylation, suggesting an epigenetic component to maternal vascular remodeling during pregnancy.
Placental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects... more Placental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects on isolated uterine arteries from nonpregnant and mid-pregnant rats. Vessels were isolated, cannulated, and pressurized to 50 mmHg within an arteriograph, preconstricted and exposed to increasing PP13 concentrations (10 −13-10 −8 M). PP13 elicited 38-50% arterial vasodilation with half-maximum response (EC 50) = 1 pM. The relaxation was mediated by activating the endothelialsignaling pathways of prostaglandin and nitric oxide (NO). Accordingly, these results encourage evaluation of PP13 as a possible therapy for gestational diseases characterized by insufficient uteroplacental blood flow and/or maternal hypertension.
Purpose of Review The goal of this review is to present the newest insights into what we view as ... more Purpose of Review The goal of this review is to present the newest insights into what we view as a central failure of cardiovascular adaptation in preeclampsia (PE) by focusing on one clinically significant manifestation of maternal endothelial dysfunction: nitric oxide signaling. The etiology, symptoms, and current theories of the PE syndrome are described first, followed by a review of the available evidence, and underlying causes of reduced endothelial nitric oxide (NO) signaling in PE. Recent Findings PE maladaptations include, but are not limited to, altered physiological stimulatory inputs (e.g., estrogen; VEGF/PlGF; shear stress) and substrates (L-Arg; ADMA), augmented placental secretion of anti-angiogenic and inflammatory factors such as sFlt-1 and Eng, changes in eNOS (polymorphisms, expression), and reduced bioavailability of NO secondary to oxidative stress. Summary PE is a complex obstetrical syndrome that is associated with maternal vascular dysfunction. Diminished peripheral endothelial vasodilator influence in general, and of NO signaling specifically, are key in driving disease progression and severity.
Background The regulation of vascular tone in the uterine circulation is a key determinant of app... more Background The regulation of vascular tone in the uterine circulation is a key determinant of appropriate uteroplacental blood perfusion and successful pregnancy outcome. Estrogens, which increase in the maternal circulation throughout pregnancy, can exert acute vasodilatory actions. Recently a third estrogen receptor named GPER (G protein-coupled estrogen receptor) was identified and, although several studies have shown vasodilatory effects in several vascular beds, nothing is known about its role in the uterine vasculature.
and/or altered physical forces secondary to adaptive changes in arterial diameter. These differen... more and/or altered physical forces secondary to adaptive changes in arterial diameter. These differences implicate pregnancy-specific pathways in the development and inhibition of myogenic tone, and point to potentially opposing roles of NO and hypertension.
Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of ... more Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of neurofilaments are seen in several neurodegenerative diseases, and this suggests that neurofilament transport is defective. Excitotoxic mechanisms involving glutamate are believed to be part of the pathogenic process in some neurodegenerative diseases, but there is currently little evidence to link glutamate with neurofilament transport. We have used a novel technique involving transfection of the green fluorescent proteintagged neurofilament middle chain to measure neurofilament transport in cultured neurons. Treatment of the cells with glutamate induces a slowing of neurofilament transport. Phosphorylation of the side-arm domains of neurofilaments has been associated with a slowing of neurofilament transport, and we show that glutamate causes increased phosphorylation of these domains in cell bodies. We also show that glutamate activates members of the mitogen-activated protein kinase family, and that these kinases will phosphorylate neurofilament side-arm domains. These results provide a molecular framework to link glutamate excitotoxicity with neurofilament accumulation seen in some neurodegenerative diseases.
To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling duri... more To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling during pregnancy, mice were injected with anti-FLT1 neutralizing antibody (Ab) beginning on Gestational Day 8 or 12 and every other day thereafter until Day 18; vehicle-only injected mice served as controls. Uterine artery blood flow was measured with ultrasound on Days 13 and 18, and morphometric measurements of the uterine arcade were carried out on Day 19 to provide a measure of gestational vascular remodeling; reproductive performance was evaluated by determining litter size, resorption rates, and pup and placental weights. Ab injections beginning on Day 8 or Day 12 resulted in significant reductions of uterine artery peak systolic and diastolic flows at Days 13 and 18. In addition, normal reproductive function was compromised, as evidenced by a significant reduction in average number of viable pups along with enhanced resorption rates. Reproductive performance was also significantly compromised in this group, although less severely. There was no evidence of a reduction in main uterine artery diameters, though arterial distensibility was reduced, and the diameter of the main uterine vein was significantly smaller in the Ab-injected mice. Significant reductions in main uterine artery and segmental artery length were also noted. Placental and pup weights were similar in all the groups. FLT1 inhibition during murine pregnancy impaired blood flow to the fetalplacental unit, compromised several indices of vascular remodeling, reduced fecundity, and increased fetal reabsorptions. The effects of FLT1 inhibition are most pronounced when targeted during early pregnancy.
Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery ou... more Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery outward circumferential remodeling during pregnancy. Although the underlying mechanisms are not known, they likely involve matrix metalloproteinases (MMPs). The goal of this study was to examine the linkage among NO inhibition, expansive remodeling, and MMP expression within the uterine vascular wall. Adult female rats were treated with NG-nitro-l-arginine methyl ester [l-NAME (LPLN)] beginning on day 10 of pregnancy and until death at day 20 and compared with age-matched controls [late pregnant (LP)]. Mean arterial pressure of LPLN rats was significantly higher than controls. LPLN fetal and placental weights were significantly reduced compared with controls. Main uterine arteries (mUA) were collected to determine dimensional properties (lumen area and wall thickness), collagen and elastin content, and levels of endothelial nitric oxide synthase (eNOS) and MMP expression. Circumferential r...
Increased pressure-induced (myogenic) tone in small uteroplacental arteries from late pregnant (L... more Increased pressure-induced (myogenic) tone in small uteroplacental arteries from late pregnant (LP) rats has been previously observed. In this study, we hypothesized that this response may result from a diminished activity of vascular smooth muscle cell (SMC) voltage-gated delayed-rectifier K+ (Kv) channels, leading to membrane depolarization, augmented Ca2+ influx, and vasoconstriction (tone). Elevation of intraluminal pressure from 10 to 60 and 100 mmHg resulted in a marked, diltiazem-sensitive rise in SMC cytosolic Ca2+ concentration ([Ca2+]i) associated with a vasoconstriction of uteroplacental arteries of LP rats. In contrast, these changes were significantly diminished in uterine arteries from nonpregnant (NP) rats. Gestational augmentation of pressure-induced Ca2+ influx through L-type Ca2+ channels was associated with an enhanced SMC depolarization, the appearance of electrical and [Ca2+]i oscillatory activities, and vasomotion. Exposure of vessels from NP animals to 4-amino...
American Journal of Obstetrics and Gynecology, 2002
OBJECTIVE: This study characterized the cellular remodeling that contributes to uterine venous gr... more OBJECTIVE: This study characterized the cellular remodeling that contributes to uterine venous growth during gestation and evaluated the effect of pregnancy on the mechanical properties of the uterine vein. STUDY DESIGN: Diameter and distensibility were calculated in pressurized uterine veins from virgin and pregnant (19-20 days of gestation) rats; the rates of cellular division (endothelial, vascular smooth muscle) were quantified with an intraperitoneal bromodeoxyuridine injection and immunohistochemistry. Elastin content, adrenergic nerve density, and wall thickness were determined in fixed uterine veins and quantified with an imaging program. RESULTS: There was a statistically significant increase in the diameter and mitotic indices (endothelial, vascular smooth muscle) in uterine veins from late pregnant versus nonpregnant animals. Adrenergic nerve density was diminished significantly during gestation. Venous distensibility increased during pregnancy, with an associated reduction in elastin content. CONCLUSION: Pregnancy results in coordinated and multifaceted structural remodeling of uterine veins with subsequent changes in caliber, mechanical properties, rates of cellular division, adrenergic innervation, and matrix composition.
Uploads
Papers by George Osol