Resistance Vessels Research Articles

Maternal adiponectin restores cholinergic vasodilation in resistance vessels from adult offspring exposed to maternal obesity in utero.

Maternal obesity increases the risk of cardiovascular and metabolic disease in the offspring both during childhood and adult life. Pregnant women and mice with obesity have lower circulating levels of adiponectin (ADN) compared to lean controls. ADN is an adipokine involved in regulating energy metabolism, vascular function, and placental function. We hypothesized that offspring of obese mice have impaired resistance artery function, which can be prevented by restoration of normal circulating ADN levels in obese dams during late pregnancy. Adult female mice were fed either control or obesogenic diet and mated with control diet-fed males. Control dams received a continuous infusion of phosphate saline buffer (PBS) during late pregnancy whereas obese females received either PBS or ADN. After weaning, offspring were fed a control diet. Mesenteric arteries (MsA) were dissected from adult offspring and mounted in a wire myograph or fixed for histology. MsA responses to vasoconstrictors (phenylephrine and endothelin-1) were not different between infusion groups. However, the vasodilatory responses to acetylcholine were reduced in offspring from obese dams as compared to control-fed dams. ADN supplementation during pregnancy restored the cholinergic vasodilatory responses of resistance vessels in offspring from obese dams. These observations suggest a target during obese pregnancy for the prevention of the long-lasting vascular effects in the offspring.

Impact of Corticosteroid Administration on Fetal Doppler Metrics and Neonatal Outcomes: A Comprehensive Review

Abstract Antenatal corticosteroid therapy is a crucial intervention to improve neonatal outcomes in pregnancies at risk of preterm birth. Corticosteroids such as betamethasone and dexamethasone enhance fetal lung maturation and reduce morbidity and mortality. To assess the effects of these drugs, we conducted a systematic review adhering to PRISMA guidelines. Data were located through extensive searches of PubMed, MEDLINE, Cochrane Library, Scopus, and Web of Science, using keywords such as “antenatal corticosteroids,” “fetal Doppler,” and “neonatal outcomes,” and applying filters for human studies published between 2013 and 2024. Studies were selected based on inclusion criteria that prioritized original research articles, systematic reviews, and meta-analyses in English. Screening and eligibility assessments were performed by independent reviewers, with full-text articles. Data extraction involved recording study designs, sample sizes, corticosteroid regimens, Doppler metrics assessed, and neonatal outcomes observed. The extracted data were synthesized qualitatively through narrative methods and quantitatively using meta-analysis where applicable. The review found that corticosteroid administration leads to transient reductions in the resistance and pulsatility indices of key fetal vessels, reflecting improved placental and cerebral perfusion. These Doppler changes correlate with better neonatal outcomes, including reduced respiratory distress syndrome and enhanced neurodevelopmental results. Despite these promising findings, limitations such as small sample sizes and short follow-up periods were noted. Future research should focus on larger, multicenter trials and long-term outcome assessments. Clinicians are advised to incorporate serial Doppler monitoring in high-risk pregnancies to optimize maternal-fetal management and neonatal outcomes.

B-flow/spatiotemporal image correlation M-mode ultrasound provides novel method to quantify spiral artery remodeling during normal human pregnancy.

During human pregnancy, placental extravillous trophoblasts replace vascular smooth muscle and elastic tissue within the walls of the uterine spiral arteries, thereby remodeling them into distensible low-resistance vessels to promote placental perfusion. The present study determined whether B-flow/spatiotemporal image correlation (STIC) M-mode ultrasonography provides an in-vivo imaging method able to digitally quantify spiral artery luminal distensibility as a physiological index of spiral artery remodeling during the advancing stages of normal human pregnancy. A prospective, longitudinal, observational study was conducted to quantify spiral artery distensibility (i.e. vessel luminal diameter at systole minus diameter at diastole) by B-flow/STIC M-mode ultrasonography during the first, second and third trimesters in 290 women exhibiting a normal pregnancy. Maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), growth factors that modulate important events in spiral artery remodeling, were quantified in a subset of the women in the first, second and third trimesters of pregnancy. Median (interquartile range (IQR)) spiral artery distensibility increased progressively between the first (0.17 (0.14-0.21) cm), second (0.23 (0.18-0.28) cm) and third (0.26 (0.21-0.35) cm) trimesters of pregnancy (P < 0.0001 for all). Median (IQR) spiral artery volume flow increased progressively between the first (2.49 (1.38-4.99) mL/cardiac cycle), second (3.86 (2.06-6.91) mL/cardiac cycle) and third (7.79 (3.83-14.98) mL/cardiac cycle) trimesters (P < 0.001 for all). In accordance with the elevation in spiral artery distensibility, the median (IQR) ratio of serum PlGF/sFlt-1 × 103 levels increased between the first (7.2 (4.5-10.0)), second (22.7 (18.6-42.2)) and third (56.2 (41.9-92.5)) trimesters (P < 0.001 for all). The present study shows that B-flow/STIC M-mode ultrasonography provides an in-vivo imaging technology to quantify digitally the structural and physiological expansion of the walls of the spiral arteries during the cardiac cycle as a consequence of their transformation into compliant vessels during advancing stages of normal human pregnancy. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Beneficial Effects of Cocoa Flavanols on Microvascular Responses in Young Men May Be Dependent on Ethnicity and Lifestyle.

Cocoa flavan-3-ols affect endothelium-dependent responses in resistance vessels and microcirculation has received little attention. We tested the effects of dark chocolate consumption (396 mg total flavanols/day for 3 days) in two Groups of 10 men (18-25 years; non-smokers) each comprising equal numbers of White European (WE) and South Asian (SA) ethnicity. In Group 1, dark chocolate did not affect reactive hyperaemia in forearm muscle, but augmented muscle dilatation evoked by acute mental stress, and reactive hyperaemia and acetylcholine (ACh)-evoked dilatation in cutaneous microcirculation. Conversely, in Group 2, chocolate did not affect cutaneous reactive hyperaemia or ACh-evoked dilatation, but these responses were blunted in Group 1 relative to Group 2. Further, when Groups 1 and 2 were combined, responses were blunted in SAs relative to WEs, augmented by chocolate in SAs only. In Group 2 individuals whose ACh-evoked dilatation was attenuated by nitric oxide synthase (NOS) inhibition, ACh-evoked dilatation was not altered after chocolate, but the attenuating effect of NOS inhibition was lost. Conversely, in Group 2 individuals whose ACh-evoked dilatation was enhanced by NOS inhibition, ACh-evoked dilatation was also augmented by chocolate. We propose that in resistance and microvessels of young men, cocoa flavan-3-ols preferentially augment endothelium-dependent dilator responses whose responses are depressed by familial and lifestyle factors more prevalent in SAs than Wes. Flavan-3-ols may facilitate the NOS pathway but also influence other endothelium-dependent dilators.

Investigation on Calm Water Resistance of Wind Turbine Installation Vessels with a Type of T-BOW

Given the typical characteristics of self-propulsion and jack-up wind turbine installation vessels (WTIVs), including their full and blunt hull form and complex appendages, this paper combines the model test method with the RANS-based CFD numerical prediction method to experimentally and numerically study the resistance of the optimized hull at different spudcan retraction positions. The calm water resistance components and their mechanisms of WTIVs based on T-BOW were obtained. Furthermore, using the multivariate nonlinear least squares method, an empirical formula for rapid resistance estimation based on the Holtrop method was derived, and its prediction accuracy and applicability were validated with a full-scale ship case. This study indicates that the primary resistance components of such low-speed vessels are viscous pressure resistance, followed by frictional resistance and wave-making resistance. Notably, the spudcan retraction well area, as a unique appendage of WTIVs, exhibits a significant “moonpool additional resistance” effect. Different spudcan retraction positions affect the total calm water resistance by approximately 20% to 30%. Therefore, in the resistance optimization design of WTIVs, special attention should be paid to the matching design of the spudcan structure and the hull shell plate lines in the spudcan retraction well area.

Power-Doppler Ultrasonic Imaging of Peripheral Perfusion in Diabetic Mice.

We explored the capabilities of power-Doppler ultrasonic (PD-US) imaging without contrast enhancement for monitoring changes in muscle perfusion over time. Ischemic recovery was observed in healthy and type II diabetic male and female mice with and without exercise. In separate studies, perfusion was measured during and after 5-min ischemic periods and during four-week recovery periods following irreversible femoral ligation. A goal was to assess how well PD-US estimates tracked the diabetic-related changes in endothelial function that influenced perfusion. The average perfusion recovery time following femoral ligation increased 47% in diabetic males and 74% in diabetic females compared with non-diabetic mice. Flow-mediated dilation in conduit arteries and the reactive hyperemia index in resistive vessels each declined by one half in sedentary diabetic mice compared with sedentary non-diabetic mice. We found that exercise reduced the loss of endothelial function from diabetes in both sexes. The reproducibility of perfusion measurements was limited primarily by our ability to select the same region in muscle and to effectively filter tissue clutter. PD-US measurements can precisely follow site-specific changes in skeletal muscle perfusion related to diabetes over time, which fills the need for techniques capable of regularly monitoring atherosclerotic changes leading to ischemic vascular pathologies.

A true double-body method based on porous media model for simulation and froude scaling verification of an aquaculture vessel resistance

A blueprint of a novel aquaculture vessel composed of rectangular cylinders, pontoons, and nets with the capacity for self-propulsion was drawn. However, when completely different flow features are caused by non-stream shapes, resistance prediction cannot be accurately performed through conventional ship model experiments as the existing scale rules may be invalid. Besides, the existence of nets creates obstacles not only in model tests but also in numerical simulations. Therefore, resistance evaluation of the vessel with nets is very challenging. Porous media model for nets is one of feasible solutions and was validated by previously published experimental results, although a control volume was required. However, porous media model is incompatible with volume of fluid multiphase, which makes the double-body method adopted inevitably. A literally true double-body method based on porous media model was proposed. The comparison of vessels with and without a net exhibited a beneficial interaction between the net and the vessel hull, especially for nets with higher solidity. Furthermore, the Froude scaling law was adopted based on the hypothesis of Reynolds number invariance. All the full-scale resistances predicted by it in seven scale ratios demonstrated satisfactory consistency, and the relative errors grew with the increase of the scale ratios.

The significance of pulsatility indices in the middle cerebral, internal carotid, and common carotid arteries for small vessel disease in the brain: A retrospective cross-sectional study

Background and objectives. The pulsatility index (PI) indicates the resistance in distant blood vessels and the stiffness of major arteries outside the brain. For cerebral small vessel disease (CSVD), our aim is to enhance our comprehension of the Pulsatility Index (PI) in the common carotid artery (CCA), internal carotid artery (ICA), and middle cerebral artery (MCA). Materials and methods. This study is a cross-sectional retrospective research, which was conducted between January 2020 and June 2020 at the Dr. Cipto Mangunkusumo National Hospital, Indonesia. Patients were divided into groups with CSVD and without CSVD. Univariate and bivariate analyses, along with Spearman correlation and multivariate regression, were conducted to assess the mean difference. The overall score for CSVD was determined based on findings from brain MRI scans. Results. The median age of the 79 participants was 60 years (49-66). CSVD made up 54.4% of the total. The median (interquartile range) PI values for the CCA, ICA, and MCA in cases of CSVD were 1.48 (1.3-1.68), 1.12±0.3, and 1.11 (0.95-1.38), respectively. Despite this, no significant differences in PI were observed between the groups. In cases of total stroke, the PI of the CCA showed a moderate correlation with the PI of the MCA (B 0.4, p=0.001) and the PI of the ICA (B 0.34, p=0.005). However, no correlation was found between PI and either the burden of CSVD or the total score for small vessel disease. Conclusions. The pulsatility indices for the CCA, ICA, and MCA generally rise in cases of CSVD, indicating heightened resistance in distal blood vessels and increased stiffness in the large arteries outside the skull. This highlights the potential use of PI measurement as a promising adjunctive screening and evaluation tool in CSVD.

Myeloid cell-derived interleukin-6 induces vascular dysfunction and vascular and systemic inflammation.

The cytokine interleukin-6 (IL-6) plays a central role in the inflammation cascade as well as cardiovascular disease progression. Since myeloid cells are a primary source of IL-6 formation, we aimed to generate a mouse model to study the role of myeloid cell-derived IL-6 in vascular disease. Interleukin-6-overexpressing (IL-6OE) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6OE mice) overexpressing the cytokine in myeloid cells. Eight- to 12-week-old LysM-IL-6OE mice spontaneously developed inflammatory colitis and significantly impaired endothelium-dependent aortic relaxation, increased aortic reactive oxygen species (ROS) formation, and vascular dysfunction in resistance vessels. The latter phenotype was associated with decreased survival. Vascular dysfunction was accompanied by a significant accumulation of neutrophils, monocytes, and macrophages in the aorta, increased myeloid cell reactivity (elevated ROS production), and vascular fibrosis associated with phenotypic changes in vascular smooth muscle cells. In addition to elevated Mcp1 and Cxcl1 mRNA levels, aortae from LysM-IL-6OE mice expressed higher levels of inducible NO synthase and endothelin-1, thus partially accounting for vascular dysfunction, whereas systemic blood pressure alterations were not observed. Bone marrow (BM) transplantation experiments revealed that vascular dysfunction and ROS formation were driven by BM cell-derived IL-6 in a dose-dependent manner. Mice with conditional overexpression of IL-6 in myeloid cells show systemic and vascular inflammation as well as endothelial dysfunction. A decrease in circulating IL-6 levels by replacing IL-6-producing myeloid cells in the BM improved vascular dysfunction in this model, underpinning the relevant role of IL-6 in vascular disease.

HbA1c and Pulsatility Index in Middle Cerebral Artery of Patients with Acute Thrombotic Stroke

Highlights:1. The findings of this study indicate that clinicians should remain vigilant, as effective glycemic control, reflected by optimal HbA1c levels, does not necessarily correlate with favorable distal cerebrovascular resistance, as measured by pulsatility index (PI).2. This study recommends that patients with acute thrombotic stroke undergo a comprehensive examination to ensure an accurate diagnosis and appropriate treatment. Abstract Stroke is the second leading cause of death and disability in the world. Diabetes mellitus is a risk factor for stroke with an increase in blood viscosity associated with hyperglycemia, and HbA1c is a well-established biomarker primarily used for the long-term monitoring of glycemic control in patients with diabetes mellitus. The Pulsatility index (PI) parameter of Trans Cranial Doppler (TCD) can measure blood vessel resistance. This study was to prove the correlation between HbA1c and PI in Middle Cerebral Artery (MCA) of acute thrombotic stroke patients. A cross-sectional study was conducted to thrombotic stroke patients treated at the neurological ward of Dr. Soetomo General Academic Hospital, Surabaya, Indonesia from March 2019 to April 2020 who met the inclusion and exclusion criteria. Data were obtained from medical records. Statistical analysis was performed using Spearman test for numerical data and Chi-square for categorical data with a significant value of p &lt;0.05. There were 32 subjects who met the inclusion and exclusion criteria. A total of 24 subjects (75%) were males and 8 (25%) females with a mean age of 56.41±13.22 years. PI MCA results were abnormal in 14 subjects (43.75%) with an average of 1.8±0.97 and PI MCA was normal in 18 subjects (56.25%) with an average of 0.87±0.15. The average HbA1c was 6.55±1.9%. There was no statistically significant association observed between HbA1c and PI in MCA examination (r=0.07; p=0.73). In conclusion, the findings of this study indicate the lack of correlation between pulsatility index and HbA1c in patients with acute ischemic stroke. This underscores the importance of comprehensive cerebrovascular evaluation regardless of HbA1c status.

Protein disulfide isomerase-mediated transcriptional upregulation of Nox1 contributes to vascular dysfunction in hypertension.

Nox1 signaling is a causal key element in arterial hypertension. Recently, we identified protein disulfide isomerase A1 (PDI) as a novel regulatory protein that regulates Nox1 signaling in VSMCs. Spontaneously hypertensive rats (SHR) have increased levels of PDI in mesenteric resistance arteries compared with Wistar controls; however, its consequences remain unclear. Herein, we investigated the role of PDI in mediating Nox1 transcriptional upregulation and its effects on vascular dysfunction in hypertension. We demonstrate that PDI contributes to the development of hypertension via enhanced transcriptional upregulation of Nox1 in vascular smooth muscle cells (VSMCs). We show for the first time that PDI sulfenylation by hydrogen peroxide contributes to EGFR activation in hypertension via increased shedding of epidermal growth factor-like ligands. PDI also increases intracellular calcium levels, and contractile responses induced by ANG II. PDI silencing or pharmacological inhibition in VSMCs significantly decreases EGFR activation and Nox1 transcription. Overexpression of PDI in VSMCs enhances ANG II-induced EGFR activation and ATF1 translocation to the nucleus. Mechanistically, PDI increases ATF1-induced Nox1 transcription and enhances the contractile responses to ANG II. Herein we show that ATF1 binding to Nox1 transcription putative regulatory regions is augmented by PDI. Altogether, we provide evidence that HB-EGF in SHR resistance vessels promotes the nuclear translocation of ATF1, under the control of PDI, and thereby induces Nox1 gene expression and increases vascular reactivity. Thus, PDI acts as a thiol redox-dependent enhancer of vascular dysfunction in hypertension and could represent a novel therapeutic target for the treatment of this disease.

Right Ventricular Function and Oxidative Stress Improve with the Administration of Thyroid Hormones and Grape Juice in a Pulmonary Hypertension Model.

Adverse remodeling of lung vessels elevates pulmonary pressure and provokes pulmonary arterial hypertension (PAH). PAH results in increased right ventricle (RV) afterload, causing ventricular hypertrophy and the onset of heart failure. There is no specific treatment for maladaptive RV remodeling secondary to PAH. This study aims to explore two therapeutic approaches, grape juice (GJ) and thyroid hormones (TH), on PAH-induced oxidative stress and cardiac functional changes. Parameters of echocardiography related to lung vessel resistance (AT/ET ratio), RV contractility (TAPSE), and RV diastolic function (E/A peaks ratio) were evaluated. Also, total ROS, lipid peroxidation, antioxidant enzymes, calcium handling proteins, pro-oxidant and antioxidant protein expression were measured. Values of p<0.05 were considered statistically significant. Both GJ and TH treatments demonstrated reductions in pulmonary resistance (~22%) and improvements in TAPSE (inotropism ~11%) and AT/ET ratio (~26%) (p<0.05). There were no changes amongst groups regarding the E/A peak ratio. Although ROS and TBARS were not statistically significant, GJ and TH treatments decreased xanthine oxidase (~49%) levels and normalized HSP70 and calcium handling protein expression (p<0.05). However, only TH treatment ameliorated diastolic function (~50%) and augmented NRF2 immunocontent (~48%) (p<0.05). To the best of our knowledge, this study stands as a pioneer in showing that TH administered together with GJ promoted functional and biochemical improvements in a PAH model. Moreover, our data suggest that GJ and TH treatments were cardioprotective, combined or not, and exhibited their beneficial effects by modulating oxidative stress and calcium-handling proteins.

#2368 GHRH levels and AhR expression in CKD patients before and after kidney transplantation

Abstract Background and Aims Chronic kidney disease (CKD) is an irreversible decline in renal function where kidney transplantation (KT) is the optimal therapeutic intervention. We aim to investigate the role and activation of the uremic toxin receptor aryl hydrocarbon receptor (AhR) in the microvasculature, particularly its implication in the blood-brain barrier impairment. We will also explore the potential role of growth hormone-releasing hormone (GHRH) as a biomarker reflecting the resolution of uremia-induced inflammation, early vascular ageing (EVA) phenotype, and potential enhancement in central nervous system (CNS) function post-KT. Method Resistance arteries from KT patients and non-CKD controls were isolated and expression of AhR was analysed by immunohistochemistry. The study used plasma samples from 60 KT patients, and levels of GHRH were measured at baseline and two years after transplantation using ELISA. Results Following KT, our initial findings indicate a decrease in levels of DBP, Lp(a), creatinine, homocysteine, phosphate, and troponin T among KT patients. Conversely, there was an increase in albumin, HBA1c, calcium and NfL post-transplantation. The expression of AhR in the resistance arteries of KT patients (2.6%) was notably lower compared to non-CKD controls (9.7%). Plasma concentrations of GHRH were significantly higher (p &amp;lt; 0.0001) in CKD-5 patients two years post-KT (2.94 ng/mL, IQR 2.60-3.43) compared to baseline (2.32 mg/L, IQR 1.84-3.24). This elevated trend in GHRH levels post-KT was observed in both sexes, with males (p &amp;lt; 0.0001) and females (p 0.0084) showing higher levels—males (3.0 ng/mL, IQR 2.6-3.5) and females (2.8 ng/mL, IQR 2.4-3.5)—compared to baseline level of males (2.4 ng/mL, IQR 1.8-3.2) and females (2.2 ng/mL, 1.9-3.3). No significant difference in GHRH levels was observed when assessing extreme EVA phenotypes based on the presence or absence of calcification or fibrosis. Conclusion Contrary to our initial expectation, the preliminary results indicate a downregulation in AhR expression within resistance vessels of CKD patients, implying modifications in AhR signaling within the uremic environment. The observed alteration in GHRH levels presents a promising avenue for further investigation focusing on its possible application as a biomarker for assessing CNS status in CKD patients undergoing KT. Prospective clinical application could involve the administration of GHRH agonists as a protective measure against cognitive impairment, considering its deficiency in CKD. Such supplementation holds promise to prevent further cognitive morbidity. The modulation in the levels of this hormone has the potential to significantly influence the treatment trajectory of CKD patients and enhance clinical outcomes.

Optimizing the functional state of the cardiorespiratory system of female students aged 17-19 with the help of a modified program of distance classes in physical education

The article deals with the peculiarities of the impact of a modified program of distance training on physical education on the functional state of circulatory systems and external breathing of students of 17-19 years of higher education. The relevance and practical importance of this study is due to the complex modern conditions of life of our country, the inability to conduct full -fledged classes among student youth and the need to maintain the optimal level of physical and functional state of student youth. The use among female students of the experimental group of the program of remote classes proposed by us contributed to significantly higher rates of improvement in heart rate, all types of blood pressure, Robinson's index, total peripheral resistance of blood vessels, coefficient of efficiency of blood circulation, vital capacity of the lungs (in 2-3 times), breath retention time on inhalation and exhalation (3 and 5 times, respectively), Skibinsky index 5 times, hypoxia index (20 times) and almost 5 times the levels of the functional state of the cardiovascular system and the external system breath. The results of changes in their intragroup distribution by the levels of levels of functional state of circulatory and external respiration, which were reflected in the increase of their representation in functional classes high and above average, were significantly more optimal in the experimental group. Similar changes in the girls of the control group were insignificant. The results testified to the high efficiency of the proposed program of distance classes with the use of fitness and the possibility of its practical use among students of higher education.

Internal carotid artery rupture during endovascular thrombectomy in patients with tandem occlusion: A two-case report.

Endovascular thrombectomy in patients with tandem occlusions can rarely result in the rupture of the internal carotid artery, leading to subarachnoid haemorrhage and death. However, this complication and its causes are rarely reported and discussed in the literature. We describe two cases of internal carotid artery rupture during endovascular thrombectomy in patients with tandem occlusion. It is hypothesised that the primary approach to the distal lesion, before recanalization, creates a blind alley that faces an intraluminal pressure increase upon manual contrast injection, surpassing the vessel's resistance and resulting in arterial wall rupture. To prevent this complication, approaches such as treating the proximal occlusion first, injecting the contrast through a microcatheter or retracting the endovascular support catheter proximally to the stenosis of the cervical internal carotid artery have been suggested and are discussed.

Abstract 1078: A Cross-species Platform And Phosphoproteomics Analysis To Mitigate Vegfri-induced Hypertension And Endothelial Dysfunction

Introduction: Vascular endothelial growth factor receptor inhibitors (VEGFRis) are a class of tyrosine kinase inhibitors (TKIs) used to treat human and canine cancers, but these drugs also cause hypertension (HTN) and endothelial cell (EC) dysfunction. Purpose: We combined phosphoproteomic analysis in ECs with a cross-species in-vitro and in-vivo approach to identify mitigating therapies for VEGFRi-induced EC dysfunction and HTN. Methods and Results: We developed a sorafenib-induced HTN mouse model showing increased blood pressure, mesenteric resistance vessel EC dysfunction (decreased phosphorylation of Ser1177 on endothelial nitric oxide synthase [p-eNOS], increased endothelin-1 [ET-1]), and renal glomerular endotheliosis. Human umbilical vein ECs were treated with VEGFR TKIs, non-VEGFR TKIs, and cardiovascular drugs. Phosphoproteomic mass spectrometry and a marker selection algorithm identified a 14-phosphopeptide signature differentiating VEGFR TKIs from non-VEGFR TKIs. The signature peptide RBM17 pS222 increased with VEGFRi treatment in human, canine, and mouse aortic ECs, correlating with reduced p-eNOS. By screening for cardiovascular drugs that reverse the VEGFRi phosphoproteomic signature, we found alpha-adrenergic antagonists, particularly doxazosin, had the most anti-correlated signatures. Doxazosin prevented VEGFRi-induced EC dysfunction in primary aortic ECs across species. In mice, doxazosin reversed sorafenib-induced EC dysfunction in resistance vessels without affecting blood pressure or renal glomerular endotheliosis. Conversely, lisinopril reduced HTN and glomerular endotheliosis but not EC dysfunction. Preliminary results from our clinical trial in canine cancer patients confirmed that toceranib induced HTN and showed that both doxazosin and lisinopril significantly lowered blood pressure in dogs with cancer and VEGFRi-induced HTN. Conclusion: Our study demonstrates the utility of phosphoproteomics and cross-species analysis in identifying EC-protective effects of doxazosin in VEGFRi-induced HTN. Our mouse data suggest distinct mechanisms for VEGFRi-induced EC dysfunction and HTN, potentially involving renal glomerular damage.

Effects of Myocardial Infarction-induced Heart Failure on Diaphragm Arteriolar Vasorelaxation

INTRODUCTION: Diaphragm atrophy and contractile dysfunction are prevalent in heart failure (HF), diminishing physical capacity and quality of life. The delivery of blood flow and oxygen necessary to support the metabolic demand of contractions is largely governed by the resistance vasculature (i.e., arterioles) with the endothelium playing a central role in arteriolar vasorelaxation. Adequate perfusion and blood flow distribution, and thus resistance vessel vasodilation, is a major determinate of diaphragm contractile function. While the mechanistic bases of HF-induced diaphragm dysfunction continue to be elucidated, the impact of HF on diaphragm vasomotor control has not been investigated. METHODS: Adult (6 mo) Sprague-Dawley rats (n=7) were divided into two groups: 1) Healthy Control (HC; n=4) and 2) MI-induced heart failure (HF; n=3). First-order arterioles (1A) from the medial costal diaphragm were isolated, cannulated, and pressurized at 90 cmH2O and allowed to equilibrate for 60 min to develop spontaneous tone. Thereafter, endothelium-dependent and -independent vasorelaxation responses to cumulative doses of acetylcholine (ACh; 10−9 to 10−4M) and sodium nitroprusside (SNP; 10−9 to 10−4M) were determined. RESULTS: There were no differences in spontaneous development (%) or maximal diameter (μm) between HC (20 ± 4%; 178 ± 11 μm) and HF (18 ± 2%; 184 ± 29 μm) diaphragm 1As ( P &gt; 0.05). Maximal ACh-mediated relaxation (%) was significantly reduced in HF rats compared to HC rats (52 ± 2 versus 68 ± 5%; P &lt; 0.05). Maximal endothelial-independent vasorelaxation with SNP, was not different between HC and HF rats (71 ± 3 versus 73 ± 1%; P &gt; 0.05). CONCLUSION: The preliminary data herein demonstrate that HF impaired endothelial function and vasomotor function in the medial costal diaphragm resistance vasculature. This suggests that, in HF, there may be a redistribution of blood flow to less effcient regions of the diaphragm (e.g., ventral costal) to sustain contractile function and compensate for the diminished medial costal vasomotor function demonstrated herein. Studies including a larger sample size are warranted to investigate the impact of HF on regional blood flow distribution and resistance vessel function in the diaphragm. Such investigations would yield novel mechanistic insights into HF-induced diaphragm dysfunction. National Institute of Aging 1R15AG078060, Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute 1F31HL167618-01, and Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants at Kansas State University. This is the full abstract presented at the American Physiology Summit 2024 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.

Novel Role of YAP1 in Regulating Blood Pressure and Vascular Tone

Introduction: Hypertension is a major risk factor for occlusive vascular diseases, myocardial infarction, heart failure, stroke, and chronic kidney disease. In the U.S., ~30% of adults suffer from hypertension. Merely half of the individuals with hypertension have their blood pressure under control, despite the wide range of antihypertensive medications available, indicating an urgent need for a better understanding of the underlying causes of hypertension to identify novel therapeutic strategies for its treatment and prevention. Recent genome-wide association study (GWAS) has identified an unexpected association between a loss-of-function SNP in the YAP1 gene locus and decreased blood pressure (BP). Moreover, de novo analysis of publicly available RNAseq data revealed that the vascular tissues of hypertensive mice treated with Ang-II exhibit increased YAP1 expression. Suggesting a novel role of YAP1 in blood pressure regulation. However, whether Vascular smooth muscle cell (VSMC) expressed YAP1 has a specific role in VSMC contraction and BP regulation remains completely unknown. Therefore, we hypothesized that YAP1 could play a key role in regulating blood pressure. Methodology: We have generated a novel inducible SM-specific- Yap1 Knockout ( YAP1 iKO) mouse model and employed a pharmacological inhibitor of YAP1, Verteporfin, to delineate the functional role of VSMC-expressed YAP1 in hypertension in regulating vascular tone and BP. Vascular reactivity experiments were performed using wire myography. BP was measured in ambulant mice via radiotelemetry. In vitro gain- and loss-of-function studies utilizing human coronary artery SMCs were conducted to examine the impact of YAP1 on contractility signaling components using western blotting. Results: Consistent with GWAS and RNAseq data, we found that YAP1 is upregulated in vascular tissues of spontaneously hypertensive rats (SHRs). Using aortic rings from WT mice, we discovered that Verteporfin significantly reduced vasoconstrictive responses to Phenylephrine or Serotonin but did not alter endothelium-dependent vasorelaxant responses to Acetylcholine, suggesting a specific role of YAP1 in VSMCs. Consistently, YAP1 iKO exhibited attenuated responses to vasoconstrictors in isolated conduit and resistance vessels. Importantly, radiotelemetry studies demonstrated for the first time that YAP1 iKO mice exhibit a hypotensive phenotype. Mechanistically, YAP1 gain- and loss-of-function studies in human VSMCs showed that YAP1 activates multiple signaling pathways that play a key role in VSMC contractility including RhoA/ROCK1/actin polymerization and PKC/ERK signaling pathways. Summary/Conclusion: This is the first study to demonstrate that inhibition of SM-specific-Yap1 expression regulates BP and vascular tone, likely via the regulation of contractile machinery components. Together, our data suggest that YAP1 is a promising novel therapeutic target for ameliorating hypertension. This work is supported by a grant from National Heart, Lung, and Blood Institute (R00HL153896). This is the full abstract presented at the American Physiology Summit 2024 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.

PDGFRALPHA ACTIVATION LEADS TO BLOOD PRESSURE INCREASE AND SMALL ARTERIES MEDIAL HYPERTROPHY IN MALE MICE

Objective: Arterial remodeling is associated with vascular function alteration and with hypertension development. This remodeling is due to cells reorganization within the vascular wall and in some cases to smooth muscle cells proliferation. PDGF (Platelet-derived Growth Factor) is a major regulator of arterial remodeling and some studies suggest that PDGFRα, one of its receptors, could be activated during hypertension. Our aim is to determine the role of PDGFRα and of PDGFRα-expressing progenitor cells in vascular remodeling. Design and method: We used a tamoxifen-inducible genetic mouse model of PDGFRα constitutive activation. Blood pressure was measured by the tail-cuff method and by carotid catheter. Small mesenteric arteries reactivity was studied using ex vivo arteriography. Vascular remodeling was analyzed by immunofluorescence. Results: PDGFRα constitutive activation for 6 weeks led to a 25% increase in blood pressure (p&lt;0.05) and a 25% decrease in cardiac output in male mice (p&lt;0.05), without changes in other cardiac parameters. In these mice, small mesenteric arteries showed no alteration in contractility or endothelium-dependent and independent relaxation but an increase of media thickness, whereas larger vessels did not show structure or function alteration. Echo-doppler analyses showed an increased resistivity index of the renal artery (+13% p&lt;0.05) but not of the aorta suggesting an increased resistance of small renal arteries. The remodeling of small mesenteric arteries was characterized by an early proliferation of perivascular cells at 4 days but not of medial cells followed by the production of new smooth muscle cells after 2 weeks. Female mice did not show blood pressure increase following induction of PDGFRα constitutive activation for 6 weeks. Small mesenteric arteries showed a reduced contractility with alteration of endothelium-dependent and independent relaxation. Conclusions: These results suggest that PDGFRα activation could participate in arterial hypertension development by leading to increased media thickness and stiffness in small arteries in males. Our results suggest that in females the increased resistance of small vessels is compensated by a decreased contractility.

Effects of aging on vasoconstrictor responses of diaphragm arterioles

Introduction: In health, the diaphragm is the most important inspiratory muscle and the only skeletal muscle that is continuously recruited throughout life. Because of the diaphragm’s importance to generating the exercise hyperpnea and wealth of evidence that diaphragm fatigue and exhaustion can impair exercise tolerance, we were interested in whether the exercise intolerance that attends older populations might be associated with altered diaphragm vasomotor control. While it is known that aging compromises peripheral skeletal muscle vasomotor control, it is not known if similar impairments are present in the respiratory muscle vasculature, namely the diaphragm. Therefore, we tested the hypothesis that advanced age decreases diaphragm arteriole contractile responses to alpha-adrenergic agonists. Methods: 4–5 month old Fischer rats and 22–24 month old Fischer rats were divided by age into two groups: young (Y) and old (O). In Y and O, diaphragm first order (1A) arterioles (~200μm diameter, ~2μm in length) were isolated, cannulated, and pressurized to develop spontaneous tone. Following this, contractile responses to cumulative doses of norepinephrine (NE) and phenylephrine (PE) (10−9 to 10−4M) were determined. Results and Conclusion: The physical characteristics of the two groups differed as O were heavier than Y. However, with respect to the diaphragm 1A arterioles, there were no differences in spontaneous tone development (%) or maximal diameter (μm) between Y (38 ± 4%; 132 ± 19μm) and O (37 ± 4%; 157 ± 14 μm; both P &gt;0.05). In diaphragm 1A arterioles, the maximal vasoconstrictor response to NE was also not different between O and Y animals (O: 37 ± 8% vs. Y: 45 ± 1%; p &gt; 0.05). However, the maximal vasoconstrictor response to PE was greater in Y compared to O (O: 29 ± 3% vs. Y: 39 ± 5%; p ≤ 0.05). These data support that aging may reduce a1 adrenergic receptor mediated vascular control, altering the vasoconstrictive responsiveness of diaphragm resistance vessels. We are increasing our group sizes to test the robustness of this conclusion. This work was supported by the Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants awarded to T.I.M and D.C.P. by Kansas State University College of Veterinary Medicine and the National Institute on Aging 1R15AG078060 awarded to B.J.B and D.C.P. A.G.H and K.M.S. were financially supported by Ruth L. Kirschstein National Research Service Awards 1F31HL167618-01 and 1F31HL170643-01, respectively. This is the full abstract presented at the American Physiology Summit 2024 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.