L-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia

2021 ◽  
Author(s):  
Mary Gemmel ◽  
Elizabeth F Sutton ◽  
Judith Brands ◽  
Lauren Burnette ◽  
Marcia J Gallaher ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mouse Model ◽  
Vascular Function ◽  
Ex Vivo ◽  
Treatment Options ◽  
Late Pregnancy ◽  
Therapeutic Effects ◽  
Specific Syndrome ◽  
Increased Risk ◽  
Pregnancy And Postpartum

Preeclampsia is a spontaneously occurring pregnancy complication diagnosed by new onset hypertension and end-organ dysfunction with or without proteinuria. This pregnancy-specific syndrome contributes to maternal morbidity and mortality and can have detrimental effects on fetal outcome. Preeclampsia is also linked to increased risk of maternal cardiovascular disease throughout life. Despite intense investigation of this disorder, few treatment options are available. The aim of this study was to investigate the potential therapeutic effects of maternal L-citrulline supplementation on pregnancy-specific vascular dysfunction in the ♀ C57BL/6J x ♂ C57BL/6J C1q-/- preeclampsia-like mouse model. L-citrulline is a non-essential amino acid that is converted to L-arginine to promote smooth muscle and blood vessel relaxation and improve nitric oxide (NO) mediated vascular function. To model a preeclampsia-like pregnancy, female C57BL/6J mice were mated to C1q-/- male mice, and a subset of dams were supplemented with L-citrulline throughout pregnancy. Blood pressure, systemic vascular glycocalyx, and ex-vivo vascular function were investigated in late pregnancy, and postpartum at 6 and 10 months of age. Main findings show that L-citrulline reduced blood pressure, increased vascular glycocalyx volume and rescued ex-vivo vascular function at gestation day 17.5 in this preeclampsia-like model. The vascular benefit of L-citrulline also extended postpartum, with improved vascular function and glycocalyx measures at 6 and 10 months of age. L-citrulline mediated vascular improvements appear, in part, attributable to NO pathway signaling. Taken together, L-citrulline supplementation during pregnancy appears to have beneficial effects on maternal vascular health which may have translational implications for improved maternal cardiovascular health.

scholarly journals Paternal deficiency of complement component C1q leads to a preeclampsia-like pregnancy in wild-type female mice and vascular adaptations postpartum

2020 ◽  
Vol 318 (6) ◽  
pp. R1047-R1057
Author(s):  
Elizabeth F. Sutton ◽  
Mary Gemmel ◽  
Judith Brands ◽  
Marcia J. Gallaher ◽  
Robert W. Powers
Keyword(s):  
Vascular Function ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Late Gestation ◽  
Mesenteric Arteries ◽  
Wild Type ◽  
Specific Syndrome ◽  
Increased Risk ◽  
Pregnancy And Postpartum ◽  
Wild Type Female

Preeclampsia is a spontaneously occurring, pregnancy-specific syndrome that is clinically diagnosed by new onset hypertension and proteinuria. Epidemiological evidence describes an association between a history of preeclampsia and increased risk for cardiovascular disease in later life; however, the mechanism(s) driving this relationship are unclear. Our study aims to leverage a novel preeclampsia-like mouse model, the C1q−/− model, to help elucidate the acute and persistent vascular changes during and following a preeclampsia-like pregnancy. Female C57BL/6J mice were mated to C1q−/− male mice to model a preeclampsia-like pregnancy (“PE-like”), and the maternal cardiovascular phenotype (blood pressure, renal function, systemic glycocalyx, and ex vivo vascular function) was assessed in late pregnancy and postpartum at 6 and 10 mo of age. Uncomplicated, normotensive pregnancies (female C57BL/6J bred to male C57BL/6J mice) served as age-matched controls. In pregnancy, PE-like dams exhibited increased systolic and diastolic pressure during mid- and late gestation, renal dysfunction, fetal growth restriction, and reduced placental efficiency. Ex vivo wire myography studies of mesenteric arteries revealed severe pregnancy-specific endothelial-dependent and -independent vascular dysfunction. At 3 and 7 mo postpartum (6 and 10 mo old, respectively), hypertension resolved in PE-like dams, whereas mild vascular dysfunction persisted at 3 mo postpartum. In conclusion, the female C57BL/6J-by-male C57BL/6J C1q−/− model recapitulates many aspects of the human preeclampsia syndrome in a low-risk, wild-type female mouse. The pregnancy-specific phenotype results in systemic maternal endothelial-dependent and -independent vascular dysfunction that persists postpartum.

scholarly journals Investigation of a Paternal-Mediated Preeclampsia-Like Pregnancy Phenotype Mouse Model

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Lauren Burnette ◽  
Mary Gemmel ◽  
Marcia Gallaher ◽  
Robert Powers
Keyword(s):  
Blood Pressure ◽  
Mouse Model ◽  
Genetic Control ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Neonatal Morbidity ◽  
Late Pregnancy ◽  
Similar Data ◽  
Specific Syndrome ◽  
Pregnant Mice

Preeclampsia, a pregnancy specific syndrome characterized by new onset hypertension and proteinuria, is a leading cause of maternal and neonatal morbidity and mortality. While no animal model perfectly mimics the human syndrome, breeding C1q-/- (male) to C57 (female) mice results in a preeclampsia-like pregnancy including pregnancy-specific hypertension, vascular dysfunction and altering placental phenotype. As the placental genotype is primarily paternally driven, lack of paternal C1q is likely driving this preeclampsia-like phenotype. However, more work is needed to investigate whether a lack of maternal C1q also contributes to this preeclampsia-like phenotype. The aim of this study was to investigate the pregnancy phenotype of genetic control (C1q-/- female bred to C57 male) mice. Blood pressure was monitored during pregnancy and vascular function assessed during late pregnancy (gestation day 17.5) in genetic control females. These data were compared to similar data obtained from control (C57 male bred to C57 female) and preeclampsia-like (C1q-/- male bred to C57 female) pregnant mice. Genetic control blood pressure and vascular function data were similar to that of the control pregnancy group, indicating no significant effect of maternal C1q deficiency on the “preeclampsia-like” pregnancy phenotype. As understanding preeclampsia and its effect on women’s health is critical, the work presented is important to confirm the C1q-/- x C57 mouse model as a useful model for studying this syndrome further.

Altered stress hormone levels affect in vivo vascular function in the hAPP23+/- overexpressing mouse model of Alzheimer's disease

2021 ◽  
Author(s):  
Jhana O. Hendrickx ◽  
Sofie De Moudt ◽  
Debby Van Dam ◽  
Peter Paul De Deyn ◽  
Paul Fransen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Blood Pressure ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Systolic Blood Pressure ◽  
Vascular Function ◽  
Ex Vivo ◽  
Stress Hormone ◽  
Hormone Levels

Alzheimer's disease (AD) has long been considered a brain-specific dementia syndrome. However, in recent decades the occurrence of cardiovascular (CV) disease in the progression of AD has been confirmed by increasing epidemiological evidence. In this study, we conducted an in-depth cardiovascular characterization of a humanized APP overexpressing mouse model (hAPP23+/-), which overexpresses the Swedish mutation (KM670/671NL). At the age of 6 months, hAPP23+/- mice had a lower survival, lower body weight and increased corticosterone and VMA levels compared to C57BL/6 littermates. Systolic blood pressure was increased in hAPP23+/- animals compared to C57BL/6 littermates, but diastolic blood pressure was not statistically different. Pulse pressure remained unchanged but abdominal and carotid pulse wave velocity (aPWV and cPWV) were increased in hAPP23+/- compared to C57BL/6 mice. Echocardiography showed no differences in systolic or diastolic cardiac function. Ex vivo evaluation of vascular function showed decreased adreno-receptor dependent vasoconstriction of hAPP23+/- aortic segments, although the isobaric biomechanics of the aortic wall were similar to C57BL/6 aortic segments. In conclusion, hAPP23+/- mice exhibited high serum corticosterone levels, elevated systolic blood pressure and increased arterial stiffness in vivo. However, ex vivo aortic stiffness of hAPP23+/- aortic segments was not changed and vascular reactivity to α1-adrenoceptor stimulation was attenuated. These findings highlight the need for more frequent assessment of circulating stress hormone levels and PWV measurements in daily clinical practice for people at risk of AD.

Abstract MP65: Increased Sedentary Time Is Associated With Greater Postpartum Blood Pressure In Women With A History Of Preeclampsia

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Virginia R Nuckols ◽  
Amy Stroud ◽  
Kelsey Gruber ◽  
Rumbidzai Ngonyama ◽  
Debra Brandt ◽  
...  
Keyword(s):  
Physical Activity ◽  
Blood Pressure ◽  
Aortic Stiffness ◽  
Leisure Time ◽  
Sedentary Time ◽  
Late Pregnancy ◽  
Chronic Hypertension ◽  
Increased Risk ◽  
Pregnancy And Postpartum ◽  
History Of

Introduction: Women with a history of preeclampsia (hxPE) are at a four-fold increased risk for chronic hypertension and have elevated aortic stiffness compared withhealthy pregnancy (HP). Higher sedentary time (ST) is related to higher odds of hypertension in clinic among young women regardless of the amount of moderate-to-vigorous physical activity (MVPA). As pregnancy and postpartum are uniquely vulnerable times of increased sedentary behavior, the objectives of this study were to determine whether ST is associated with higher blood pressure (BP) and aortic stiffness in women with hxPE compared with HP 1-3 years postpartum, and if change in ST from late pregnancy to postpartum is related to change in BP or aortic stiffness. Methods: Women with hxPE (N=33) and HP (N=46) completed the Pregnancy Physical Activity Questionnaire (PPAQ) 18±6 months postpartum. BP was assessed in triplicate in clinic and by 24-hour ambulatory blood pressure monitoring and aortic stiffness by carotid-femoral pulse wave velocity (CFPWV). In a subset of women (N=20), clinic BP, CFPWV and the PPAQ were previously evaluated in the third trimester. Results: Women with hxPE reported more leisure-time ST compared with HP (18 [7-19] vs 7 [5-7] MET-hr/wk, P<0.001), whereas MVPA did not differ (77 [39-106] vs 56 [35-88] MET-hr/wk, P=0.13). 24-hour ambulatory BP was higher in women with hxPE (120 [114-126] vs 114 [109-120] mmHg, P=0.049; 78 [72-82] vs 74 [70-77] mmHg, P=0.056), but CFPWV did not differ independently of BP (6.1 vs 5.5 m/s, P=0.33). Postpartum ST, but not MVPA, was associated with higher 24-hr systolic (ρ=0.24, P=0.04) and diastolic BP (ρ=0.27, P=0.02) and higher CFPWV (ρ=0.31, P=0.008) independent of body mass index. Increases in ST from late pregnancy to postpartum (0 [-3-2] ΔMET-hr/wk, P=0.22) was related to increased BP (systolic ρ=0.42, P=0.06; diastolic ρ=0.44, P=0.050) and increases in CFPWV (ρ=0.54, P=0.02) despite a reported increase in MVPA (21.5 [-0.5-63] ΔMET-hr/wk, P=0.04). Conclusions: Greater ST is related to higher BP and aortic stiffness 1-3 years postpartum, and women with hxPE report greater leisure-time ST compared with HP controls. Reduction in ST may represent an achievable interventional strategy to improve cardiovascular health in women with hxPE.

scholarly journals Optimizing cisplatin delivery to triple-negative breast cancer through novel EGFR aptamer-conjugated polymeric nanovectors

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Lisa Agnello ◽  
Silvia Tortorella ◽  
Annachiara d’Argenio ◽  
Clarissa Carbone ◽  
Simona Camorani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Tumor Targeting ◽  
Triple Negative ◽  
Ex Vivo ◽  
Treatment Options ◽  
Negative Control ◽  
Therapeutic Effects ◽  
Metastatic Setting

Abstract Background Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC. Methods Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses. Results We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs. Conclusions Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.

scholarly journals Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Shih-Yin Ho ◽  
Li Lin ◽  
I-Chun Chen ◽  
Che-Wen Tsai ◽  
Fang-Chia Chang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Model Potential ◽  
Temperature Tolerance ◽  
Epileptic Activity ◽  
Dravet Syndrome ◽  
Therapeutic Effects ◽  
Discharge Duration ◽  
Spontaneous Recurrent Seizures

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1aE1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1aE1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

scholarly journals Hydration status and hypertension in University workers

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
P Padrão ◽  
P Moreira ◽  
T Silva-Santos ◽  
S Abreu ◽  
O Pinho ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Free Water ◽  
Binary Logistic Regression ◽  
Positive Association ◽  
Hydration Status ◽  
Binary Logistic Regression Model ◽  
Cross Sectional ◽  
Arterial Blood ◽  
Increased Risk

Abstract Background Vascular function and blood pressure regulation may be impaired by acute hypohydration but data on the association between hypertension and hydration status is scarce. The objectives of this study were to evaluate the hydration status in a sample of university workers and to assess the association between hypertension and hydration status. Methods A cross-sectional evaluation of a sample of 60 university workers (32 women) was conducted in 2019/2020 in Portugal. A 24-hour urine sample was collected; urinary volume, creatinine and osmolality were quantified. Free water reserve (FWR) was used to assess hydration status and subjects were classified as hypohydrated (FWR&lt;0) or euhydrated (FWR &gt; =0). Arterial blood pressure was evaluated [average of 2 blood pressure (BP) measurements] by researchers using standard methodology and participants with systolic and diastolic blood pressure ≥130 mm Hg and/or ≥80 mm Hg, respectively, were classified as hypertensive. A binary logistic regression model was used to estimate the association between hypohydration and hypertension, adjusting for sex, age and use of anti-hypertensive drugs. Odds Ratios (OR) and respective 95% Confidence Intervals (95%CI) were calculated. Results Hypertension was observed in 40.6% of women and 67.9% of men whereas hypohydration affected 31.3% of women and 32.1% of men. After adjusting for confounders, hypertension was associated with a 7-fold increased risk of hypohydration (OR = 7.56; 95% CI: 1.81-31.59). Conclusions These results stress the positive association between hypohydration and hypertension and highlight the need for implementing strategies for the promotion of water intake, particularly in the hypertensive patients. This project was granted by Fundação para a Ciência e Tecnologia - Grant POCI-01-0145-FEDER-029269. Key messages Hypohydration affect nearly one third of this sample of university workers. Hypertension was associated with a 7-fold increased risk of hypohydration.

scholarly journals Optimizing Cisplatin Delivery to Triple-negative Breast Cancer through Novel EGFR Aptamer-conjugated Polymeric Nanovectors

2021 ◽  
Author(s):  
Lisa Agnello ◽  
Silvia Tortorella ◽  
Annachiara d'Argenio ◽  
Clarissa Carbone ◽  
Simona Camorani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Tumor Targeting ◽  
Triple Negative ◽  
Ex Vivo ◽  
Treatment Options ◽  
Negative Control ◽  
Therapeutic Effects ◽  
Metastatic Setting

Abstract Background: Management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and limited targeted treatment options. Cisplatin represents a promising chemotherapeutic compound in neoadjuvant approaches and in the metastatic setting, but its use is limited by scarce bioavailability, severe systemic side effects and drug resistance. Novel site-directed aptamer-based nanotherapeutics have the potential to overcome obstacles of chemotherapy. In this study we investigated the tumor targeting and the anti-tumorigenic effectiveness of novel cisplatin-loaded and aptamer-decorated nanosystems in TNBC.Methods: Nanotechnological procedures were applied to entrap cisplatin at high efficacy into polymeric nanoparticles (PNPs) that were conjugated on their surface with the epidermal growth factor receptor (EGFR) selective and cell-internalizing CL4 aptamer to improve targeted therapy. Internalization into TNBC MDA-MB-231 and BT-549 cells of aptamer-decorated PNPs, loaded with BODIPY505-515, was monitored by confocal microscopy using EGFR-depleted cells as negative control. Tumor targeting and biodistribution was evaluated by fluorescence reflectance imaging upon intravenously injection of Cyanine7-labeled nanovectors in nude mice bearing subcutaneous MDA-MB-231 tumors. Cytotoxicity of cisplatin-loaded PNPs toward TNBC cells was evaluated by MTT assay and the antitumor effect was assessed by tumor growth experiments in vivo and ex vivo analyses.Results: We demonstrate specific, high and rapid uptake into EGFR-positive TNBC cells of CL4-conjugated fluorescent PNPs which, when loaded with cisplatin, resulted considerably more cytotoxic than the free drug and nanovectors either unconjugated or conjugated with a scrambled aptamer. Importantly, animal studies showed that the CL4-equipped PNPs achieve significantly higher tumor targeting efficiency and enhanced therapeutic effects, without any signs of systemic toxicity, compared with free cisplatin and untargeted PNPs.Conclusion: Our study proposes novel and safe drug-loaded targeted nanosystems for EGFR-positive TNBC with excellent potential for the application in cancer diagnosis and therapy.

Abstract MP68: Association of Clinical and Subclinical Blood Pressure Elevation During Pregnancy With Maternal Health and Risk of Neonatal Low Birth Weight

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Jie Hu ◽  
Jun Li ◽  
Yang Peng ◽  
Yuanyuan Li
Keyword(s):  
Blood Pressure ◽  
Birth Weight ◽  
Maternal Health ◽  
Low Birth Weight ◽  
Gestational Hypertension ◽  
Late Pregnancy ◽  
Blood Pressure Elevation ◽  
Pressure Elevation ◽  
Elevated Liver Enzymes ◽  
Increased Risk

Introduction: Gestational hypertension is a leading cause of maternal mortality and fetal growth restriction (FGR). However, elevated maternal blood pressure at which trimester contributes to FGR is unknown, and whether gestational prehypertension (a systolic blood pressure [SBP] of 120 - 139 mmHg or a diastolic blood pressure [DBP] of 80 - 89 mmHg) is related with FGR and maternal health is not fully studied. Methods: We analyzed the relation of elevated gestational blood pressure with risk of neonatal low-birth-weight (LBW, birth weight < 2,500 g) and maternal health throughout pregnancy in 21,620 women from a birth cohort in Wuhan, China. Maternal health indicators, including SBP and DBP, were clinically measured during up to 22 antenatal visits. LBW were acquired from medical records. Linear mixed models were used to evaluate the relations of maternal SBP and DBP with LBW. Logistic regressions were used to assess the associations of SBP and DBP in late pregnancy (38.3 weeks) with LBW. Linear regressions were used to evaluate the association of prehypertension/hypertension with indicators of maternal health. Results: Gestational blood pressure increases throughout pregnancy, but a significant elevation of SBP and DBP between 15 and 25 gestational weeks were only observed for women who later delivered LBW newborns. High gestational SBP (≥ 140 mmHg) or DBP (≥ 90 mmHg) was associated with a 220% or 98% higher risk of LBW ( P < 0.03). Notably, preclinical high SBP (120 - 139 mmHg) was also associated with a 40% higher risk of LBW ( P = 0.036). At late pregnancy, elevated gestational SBP and DBP were associated with elevated liver enzymes, blood urea nitrogen, creatinine, and uric acid levels, and decreased activated partial thromboplastin time and prothrombin time. Conclusions: A fast blood pressure elevation in the second trimester may relate with increased risk of LBW. Pregnancy prehypertension was associated with not only LBW risk, but also impaired maternal liver, kidney, and coagulation functions.

scholarly journals Urocortin-2 improves right ventricular function and attenuates pulmonary arterial hypertension

2018 ◽  
Vol 114 (8) ◽  
pp. 1165-1177 ◽  
Author(s):  
Rui Adão ◽  
Pedro Mendes-Ferreira ◽  
Diana Santos-Ribeiro ◽  
Carolina Maia-Rocha ◽  
Luís D Pimentel ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Function ◽  
Treatment Options ◽  
Left Ventricular ◽  
Therapeutic Effects ◽  
Tissue Samples ◽  
Male Wistar Rats ◽  
Pulmonary Arterial

Abstract Aims Pulmonary arterial hypertension (PAH) is a devastating disease and treatment options are limited. Urocortin-2 (Ucn-2) has shown promising therapeutic effects in experimental and clinical left ventricular heart failure (HF). Our aim was to analyse the expression of Ucn-2 in human and experimental PAH, and to investigate the effects of human Ucn-2 (hUcn-2) administration in rats with monocrotaline (MCT)-induced pulmonary hypertension (PH). Methods and results Tissue samples were collected from patients with and without PAH and from rats with MCT-induced PH. hUcn-2 (5 μg/kg, bi-daily, i.p., for 10 days) or vehicle was administered to male wistar rats subjected to MCT injection or to pulmonary artery banding (PAB) to induce right ventricular (RV) overload without PAH. Expression of Ucn-2 and its receptor was increased in the RV of patients and rats with PAH. hUcn-2 treatment reduced PAH in MCT rats, resulting in decreased morbidity, improved exercise capacity and attenuated pulmonary arterial and RV remodelling and dysfunction. Additionally, RV gene expression of hypertrophy and failure signalling pathways were attenuated. hUcn-2 treatment also attenuated PAB-induced RV hypertrophy. Conclusions Ucn-2 levels are altered in human and experimental PAH. hUcn-2 treatment attenuates PAH and RV dysfunction in MCT-induced PH, has direct anti-remodelling effects on the pressure-overloaded RV, and improves pulmonary vascular function.

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