Publications

Pernomian et al.

Circulation Research — September 2025

BACKGROUND:

Small artery remodeling and endothelial dysfunction are hallmarks of hypertension. Evidence supports a likely causal association between cardiovascular diseases and endothelial-to-mesenchymal transition, a cellular transdifferentiation process in which endothelial cells (ECs) partially lose their identity and acquire mesenchymal phenotypes. EC reprogramming represents an innovative strategy in regenerative medicine to prevent deleterious effects induced by cardiovascular diseases.

METHODS:

Using partial reprogramming of ECs, via overexpression of Oct-3/4-Sox-2-Klf-4 (OSK) transcription factors, we aimed to bring ECs back to a youthful phenotype in hypertension. Primary ECs were infected with lentiviral vectors (LVs) containing the specific EC promoter Cdh5 (cadherin-5) and the reporter EGFP (enhanced green fluorescent protein) with empty vector (LV control) or LV with Oct-3/4-Sox-2-Klf-4. Confocal microscopy and Western blotting analysis were used to confirm OSK overexpression. Cellular migration, senescence, and apoptosis were evaluated. Human aortic ECs from normotensive patients and patients with hypertension were analyzed after OSK treatments for eNOS (endothelial nitric oxide synthase), NO, and genetic profile. Male and female normotensive (blood pressure normal mouse strain) and hypertensive (blood pressure high mouse strain) mice were treated with LV control or LV with Oct-3/4-Sox-2-Klf-4 and evaluated 10 days post-infection. The blood pressure, cardiac function, vascular reactivity of small arteries, and endothelial-to-mesenchymal transition inhibition were analyzed.

RESULTS:

OSK overexpression induced partial EC reprogramming in vitro, and these cells had lower migratory capability. OSK treatment of blood pressure high mouse strain mice reduced blood pressure and resistance arteries hypercontractility, via the attenuation of endothelial-to-mesenchymal transition and elastin breaks. EGFP was detected in vivo in the prefrontal cortex. OSK-treated hypertensive human aortic ECs showed high eNOS activation and NO production, with low reactive oxygen species formation. Single-cell RNA analysis showed that OSK alleviated EC senescence and endothelial-to-mesenchymal transition, restoring their phenotypes in human aortic ECs from patients with hypertension.

CONCLUSIONS:

Overall, these data indicate that OSK treatment and EC reprogramming can decrease blood pressure and reverse hypertension–induced vascular damage.

Pernomian et al.

Circulation Research — August 2025

Pernomian et al.

AJP-Heart & Circ — August 2025

Heart failure (HF) involves structural and functional impairments in ventricular filling or blood ejection, and it is a growing health burden in the United States. Sex differences in HF with mildly reduced ejection fraction (HFmrEF) have been observed, and this condition is exacerbated by endothelial cell (EC) microvascular rarefaction. HF with preserved ejection fraction (HFpEF) is more prevalent in women, with hypertension being the major risk factor. However, the mechanisms by which hypertension contributes to HFpEF development remain poorly understood. We hypothesized that male hypertensive BPH/2J (blood pressure high) mice develop HFmrEF later in life with cardiac EC rarefaction, whereas female hypertensive BPH/2J mice show HFpEF. Male and female BPN/3J (blood pressure normal or control) and BPH/2J mice were assessed for blood pressure (6 wk and 1.5 yr of age). Cardiac function was assessed by echocardiography. Cardiac EC density and stem-cell antigen-1 (SCa1)+ cells were evaluated by immunofluorescence. BPH/2J mice exhibited cardiac dysfunction at 6 wk of age, before hypertension, compared with controls. By 1.5 yr of age, BPH/2J mice were hypertensive and developed HF-like features in a sex-dependent manner. Male BPH/2J mice exhibited several characteristics of HFmrEF, whereas female BPH/2J mice developed some features of HFpEF. Cardiac EC rarefaction was observed in male BPH/2J mice. Female BPH/2J mice (1.5 yr old) retained a significant SCa1+ population in coronary arteries compared with hypertensive males. These findings establish BPH/2J mice as a novel sex-specific model of hypertension-induced features of HF, revealing distinct endothelial and progenitor cell dynamics in males and females.NEW & NOTEWORTHY Male hypertensive BPH/2J mice develop characteristics of HFmrEF and cardiac microvascular rarefaction, whereas female hypertensive BPH/2J mice recapitulate features of HFpEF. SCa1+ cells in the heart might play a role in left ventricular ejection fraction (LVEF) worsening. Preventing the loss of cardiac EC can be a strategy to reduce fibrosis and stimulate angiogenesis to improve cardiac repair in HF.

Costa et al.

AJP-Heart & Circ — May 2025

Menopause has unequivocally been associated with cardiovascular risk and obesity. Loss of estrogen bioavailability is a hallmark of menopause. Estrogen is generally considered vasculoprotective, with estrogen receptor α (ERα) being the predominant receptor subtype that mediates these positive effects. Similarly, estrogen and ERα are known to stimulate white adipose tissue metabolism. However, it is unknown whether ERα could exert a beneficial effect on mesenteric perivascular adipose tissue (PVAT). PVAT is a heterogenous tissue that surrounds most peripheral blood vessels. In physiological conditions, PVAT has an anti-contractile effect on the vasculature. However, in several diseases, PVAT switches its phenotype to become pro-contractile. To date, the role of ERα in PVAT function in health and disease is unknown. Therefore, we hypothesized that overexpression of adipose tissue ERα (ERαOE) would (i) increase the anti-contractile effect of PVAT in chow diet conditions and (ii) protect mice against a high fat diet (HFD)-induced PVAT dysfunction. To test this hypothesis, mesenteric resistance arteries, with and without PVAT, were isolated from female ERαOE mice, which had either been on a regular chow diet or a HFD for 19 weeks. We observed that ERαOE amplifies the anti-contractile effect of mesenteric PVAT via NADPH oxidase 4 (NOX4)-derived hydrogen peroxide (H2O2) in chow conditions, and ERαOE is protective against a dysfunctional PVAT that is observed after a HFD, via the same anti-contractile mechanism. Collectively, these data demonstrate that ERα is vasculoprotective in the context of PVAT. Harnessing this signaling could be important for reducing cardiovascular risk in post-menopausal women.

Waigi et al.

Geroscience — June 2024

Increasing evidence shows that cardiovascular diseases (CVDs) are associated with an increased risk of cognitive impairment and Alzheimer’s diseases (AD). It is unknown whether systemic vascular dysfunction occurs prior to the development of AD, if this occurs in a sex-dependent manner, and whether endothelial cells play a role in the deposition of amyloid beta (Aβ) peptides. We hypothesized that vascular dysfunction occurs prior to the onset of amyloid pathology, thus escalating its progression. Furthermore, endothelial cells from female mice will present with an exacerbated formation of Aβ peptides due to an exacerbated pressure pulsatility. To test this hypothesis, we used a double transgenic mouse model of early-onset AD (APPswe/PSEN1dE9). We evaluated hippocampus-dependent recognition memory and the cardiovascular function by echocardiography and direct measurements of blood pressure through carotid artery catheterization. Vascular function was evaluated in resistance arteries, morphometric parameters in the aortas, and immunofluorescence in the hippocampus and aortas. We observed that endothelial dysfunction occurred prior to the onset of amyloid pathology irrespective of sex. However, during the onset of amyloid pathology, only female APP/PS1 mice had vascular stiffness in the aorta. There was elevated Aβ deposition which colocalized with endothelial cells in the hippocampus from female APP/PS1 mice. Overall, these data showed that vascular abnormalities may be an early marker, and potential mediator of AD, but exacerbated aortic stiffness and pressure pulsatility after the onset of amyloid pathology may be associated with a greater burden of Aβ formation in hippocampal endothelial cells from female but not male APP/PS1 mice.

Eguchi et al.

Hypertension — February 2024

To celebrate 100 years of AHA-supported cardiovascular disease research, this review article highlights milestone papers that have significantly contributed to the current understanding of the signaling mechanisms driving hypertension and associated cardiovascular disorders. This article also includes a few of the future research directions arising from these critical findings. To accomplish this important mission, 4 principal investigators gathered their efforts to cover distinct yet intricately related areas of signaling mechanisms pertaining to the pathogenesis of hypertension. The renin-angiotensin system, canonical and novel contractile and vasodilatory pathways in the resistance vasculature, vascular smooth muscle regulation by membrane channels, and noncanonical regulation of blood pressure and vascular function will be described and discussed as major subjects.

Costa et al.

Clinical Science — November 2023

O-Linked attachment of β-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and ubiquitous post-translational modification that impacts the function, activity, subcellular localization, and stability of target proteins. Physiologically, acute O-GlcNAcylation serves primarily to modulate cellular signaling and transcription regulatory pathways in response to nutrients and stress. To date, thousands of proteins have been revealed to be O-GlcNAcylated and this number continues to grow as the technology for the detection of O-GlcNAc improves. The attachment of a single O-GlcNAc is catalyzed by the enzyme O-GlcNAc transferase (OGT), and their removal is catalyzed by O-GlcNAcase (OGA). O-GlcNAcylation is regulated by the metabolism of glucose via the hexosamine biosynthesis pathway, and the metabolic abnormalities associated with pathophysiological conditions are all associated with increased flux through this pathway and elevate O-GlcNAc levels. While chronic O-GlcNAcylation is well associated with cardiovascular dysfunction, only until recently, and with genetically modified animals, has O-GlcNAcylation as a contributing mechanism of cardiovascular disease emerged. This review will address and critically evaluate the current literature on the role of O-GlcNAcylation in vascular physiology, with a view that this pathway can offer novel targets for the treatment and prevention of cardiovascular diseases.

Bernardino de Paula et al.

AJP-Heart & Circ — November 2023

2022

McCarthy CG, Waigi EW, Yeoh BS, Mell B, Vijay-Kumar M, Wenceslau CF, Joe B. Low-dose 1,3-butanediol reverses age-associated vascular dysfunction independent of ketone body β-hydroxybutyrate. Am J Physiol Heart Circ Physiol. 2022 Mar 1;322(3):H466-H473. doi: 10.1152/ajpheart.00486.2021. Epub 2022 Feb 11. PubMed PMID: 35148235; PubMed Central PMCID: PMC8897007.

Costa, Tiago J.a,b; Linder, Braxton A.c; Hester, Setha,b; Fontes, Milenea,b; Pernomian, Laenaa,b; Wenceslau, Camilla F.a,b; Robinson, Austin T.c; McCarthy, Cameron G.a,b. The janus face of ketone bodies in hypertension. Journal of Hypertension 40(11):p 2111-2119, November 2022. | DOI: 10.1097/HJH.0000000000003243

Santos CVD, Kerkhoff J, Tomazelli CA, Wenceslau CF, Sinhorin AP, de Jesus Rodrigues D, Carneiro FS, Bomfim GF. Vasoconstrictor and hemodynamic effects of a methanolic extract from Rhinella marina toad poison. Toxicon. 2022 Oct 30;218:57-65. doi: 10.1016/j.toxicon.2022.08.018. Epub 2022 Sep 14. PMID: 36113683; PMCID: PMC9832923.

McCarthy CG, Waigi EW, Singh G, Castaneda TR, Mell B, Chakraborty S, Wenceslau CF, Joe B. Physiologic, Metabolic, and Toxicologic Profile of 1,3-Butanediol. J Pharmacol Exp Ther. 2021 Nov;379(3):245-252. doi: 10.1124/jpet.121.000796. Epub 2021 Sep 14. PubMed PMID: 34521698; PubMed Central PMCID: PMC9164310.

Roy S, Edwards JM, Tomcho JC, Schreckenberger Z, Bearss NR, Zhang Y, Morgan EE, Cheng X, Spegele AC, Vijay-Kumar M, McCarthy CG, Koch LG, Joe B, Wenceslau CF. Intrinsic Exercise Capacity and Mitochondrial DNA Lead to Opposing Vascular-Associated Risks. Function (Oxf). 2021;2(1):zqaa029. doi: 10.1093/function/zqaa029. Epub 2020 Nov 3. PMID: 33363281; PMCID: PMC7749784.

McCarthy CG, Chakraborty S, Singh G, Yeoh BS, Schreckenberger ZJ, Singh A, Mell B, Bearss NR, Yang T, Cheng X, Vijay-Kumar M, Wenceslau CF, Joe B. Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator. JCI Insight. 2021 Oct 22;6(20). doi: 10.1172/jci.insight.149037. PubMed PMID: 34499623; PubMed Central PMCID: PMC8564907.

McCarthy CG, Saha P, Golonka RM, Wenceslau CF, Joe B, Vijay-Kumar M. Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs). Compr Physiol. 2021 Feb 12;11(1):1575-1589. doi: 10.1002/cphy.c200020. Review. PubMed PMID: 33577121; PubMed Central PMCID: PMC9721119.

Schreckenberger ZJ, Wenceslau CF, Joe B, McCarthy CG. Mitophagy in Hypertension-Associated Premature Vascular Aging. Am J Hypertens. 2020 Sep 10;33(9):804-812. doi: 10.1093/ajh/hpaa058. Review. PubMed PMID: 32533696; PubMed Central PMCID: PMC7481986.

Cheon S, Tomcho JC, Edwards JM, Bearss NR, Waigi E, Joe B, McCarthy CG, Wenceslau CF. Opioids Cause Sex-Specific Vascular Changes via Cofilin-Extracellular Signal-Regulated Kinase Signaling: Female Mice Present Higher Risk of Developing Morphine-Induced Vascular Dysfunction than Male Mice. J Vasc Res. 2021;58(6):392-402. doi: 10.1159/000517555. Epub 2021 Sep 14. PMID: 34521095; PMCID: PMC8612963.

Wenceslau CF, McCarthy CG, Earley S, England SK, Filosa JA, Goulopoulou S, Gutterman DD, Isakson BE, Kanagy NL, Martinez-Lemus LA, Sonkusare SK, Thakore P, Trask AJ, Watts SW & Webb RC (2021). Guidelines for the measurement of vascular function and structure in isolated arteries and veins. American Journal of Physiology-Heart and Circulatory Physiology; DOI: 10.1152/ajpheart.01021.2020.

Silva CBP, Elias-Oliveira J, McCarthy CG, Wenceslau CF, Carlos D, Tostes RC. Ethanol: striking the cardiovascular system by harming the gut microbiota. Am J Physiol Heart Circ Physiol. 2021 Aug 1;321(2):H275-H291. doi: 10.1152/ajpheart.00225.2021. Epub 2021 Jun 18. PMID: 34142885; PMCID: PMC8410123.

Edwards, J. M., Roy, S., Galla, S. L., Tomcho, J. C., Bearss, N. R., Waigi, E. W., Mell, B., Cheng, X., Saha, P., Vijay-Kumar, M., McCarthy, C. G., Joe, B., & Wenceslau, C. F. (2021). FPR-1 (Formyl peptide receptor-1) activation promotes spontaneous, premature hypertension in Dahl Salt-Sensitive rats. Hypertension, 77(4), 1191–1202. https://doi.org/10.1161/hypertensionaha.120.16237

2021

2020

2023

Waigi EW, Webb RC, Moss MA, Uline MJ, McCarthy CG, Wenceslau CF. Soluble and insoluble protein aggregates, endoplasmic reticulum stress, and vascular dysfunction in Alzheimer's disease and cardiovascular diseases. Geroscience. 2023 Jun;45(3):1411-1438. doi: 10.1007/s11357-023-00748-y. Epub 2023 Feb 24. PMID: 36823398; PMCID: PMC10400528.

Pernomian L, Tan W, McCarthy CG, Wenceslau CF. Reprogramming endothelial and vascular smooth muscle cells to prevent and treat hypertension. Medical Hypotheses [Internet]. 2023 Sep 7;179:111162. Available from: https://doi.org/10.1016/j.mehy.2023.111162