Pericytes are mural cells that line capillaries throughout the brain, retina, lung, and other organs, where they support capillary homeostasis through direct contact and paracrine crosstalk with capillary endothelium. De...Pericytes are mural cells that line capillaries throughout the brain, retina, lung, and other organs, where they support capillary homeostasis through direct contact and paracrine crosstalk with capillary endothelium. Despite being described more than a century ago, their contributions to health and vascular diseases remain unclear, largely due to the difficulty of definitive identification. Their inherent plasticity, as well as shared markers and close lineage relationships with other mural cells, results in overlap in identification and underrepresentation in single-cell data sets. Emerging evidence reveals that pericytes play a critical role in the vascular remodeling characteristics of pulmonary hypertension, via mechanisms involving smooth muscle-like phenotypic switching and morphological changes influenced by hypoxia signaling, transforming growth factor-β, cyclic GMP modulation, and disrupted pericyte-endothelial communication. Recent single-cell RNA sequencing enabled the identification of a novel and specific pericyte marker, , thereby improving pericyte identification and revealing novel pericyte subtypes. In this review, we summarize historical and recent insights into pericyte morphology and function, their increasingly recognized role in pulmonary hypertension pathobiology, and the potential to unlock novel therapeutic avenues targeting pericytes.
Zhang B, Furtado JD, Andraski AB
… +7 more, Guglielmo B, Appel LJ, Wang K, Yasunaga S, Saku K, Ikewaki K, Sacks FM
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41328959
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BACKGROUND: Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary heart diseas...BACKGROUND: Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary heart disease (CHD) has been called into question. Protein-based minor HDL subspecies are emerging as novel and likely causal biomarkers, direct or inverse, for risk of CHD, diabetes, and other conditions. HDL-raising drugs such as CETP (cholesteryl ester transfer protein) inhibitors raise certain HDL subspecies that have adverse effects on CHD risk. We hypothesize that dietary unsaturated fat, protein, and carbohydrate differentially affect 15 minor protein-based HDL subspecies with diverse functionality in lipid metabolism, antioxidation, immunity, hemostasis, and protease inhibition. METHODS: We analyzed the apo (apolipoprotein) A1 concentrations of 15 minor HDL subspecies after 4 weeks on each diet in 141 participants in the OmniHeart trial (Optimal Macronutrient Intake Trial to Prevent Heart Disease), a randomized 3-period crossover, controlled feeding study. The diet rich in carbohydrate contained 58% carbohydrate, 27% fat, and 15% protein, and the diets rich in unsaturated fat and protein replaced 10% of carbohydrate with unsaturated fat or protein, respectively. RESULTS: Unsaturated fat replacing dietary carbohydrate increased concentrations of apoA1 in lipid metabolism subspecies including HDL that contains apoA2, apoE, or apoC1 that has been associated with reduced risk of CHD. Protein replacing carbohydrate increased apoE HDL, consistent with lower CHD risk, and decreased concentrations of several other HDL subspecies that were associated with higher risk of CHD including HDL that contains PLMG (plasminogen), A2M (alpha-2-macroglobulin), or apoL1. Network analysis showed connections between functional groups of HDL subspecies that are quantitatively affected by dietary macronutrients. CONCLUSIONS: Replacing dietary carbohydrate with unsaturated fat or protein raised levels of protein-based HDL subspecies associated with lower risk of CHD or lowered the levels of those associated with higher risk of CHD. Minor HDL subspecies with diverse functions may mediate the association of dietary patterns with risk of CHD. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT00051350.
The cardiovascular and hematopoietic systems are functionally interconnected through the cardio-hematopoietic axis, a dynamic signaling network that governs hematopoietic responses following cardiac injury. Traditionally...The cardiovascular and hematopoietic systems are functionally interconnected through the cardio-hematopoietic axis, a dynamic signaling network that governs hematopoietic responses following cardiac injury. Traditionally viewed primarily as a unidirectional pathway in which cardiac damage mobilizes bone marrow-derived cells to facilitate myocardial repair, emerging evidence now suggests a bidirectional model wherein cardiac-derived cues reciprocally influence hematopoietic stem and progenitor cell fate decisions within the bone marrow niche. This review synthesizes current insights into the mechanistic crosstalk between the injured heart and bone marrow, highlighting the mechanisms by which myocardial injury activates emergency hematopoiesis and immune cell mobilization to support cardiac repair, as well as how cardiac-derived inflammatory and neurohumoral signals remodel the bone marrow niche and reprogram hematopoietic stem cell lineage commitment toward a myeloid-biased, proinflammatory output that amplifies systemic inflammation that contributes to increased cardiovascular risk.
Cui A, Patel R, Bosco P
… +5 more, Akcan U, Richters E, Barrilero Delgado P, Agalliu D, Sproul AA
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41287966
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BACKGROUND: Modeling the human blood-brain barrier (BBB) is limited by the lack of robust protocols to generate induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs). Current methods...BACKGROUND: Modeling the human blood-brain barrier (BBB) is limited by the lack of robust protocols to generate induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs). Current methods generate cells that do not fully recapitulate key BMEC functions or the brain endothelial transcriptome identity. METHODS: To address this gap, we combined directed differentiation of human iPSCs into BBB-primed endothelial cells with overexpression of FOXF2 (forkhead box F2) and ZIC3 (zic family zinc finger 3), transcription factors critical for BMEC identity, to generate reprogrammed BMECs (rBMECs) from 3 iPSC lines. We performed immunofluorescence, functional analyses, and bulk RNA sequencing to characterize these cells. We cocultured rBMECs with iPSC-derived astrocytes and pericytes in the MIMETAS microfluidics platform to assess how 3-dimensional culture influences their BBB properties. Finally, we generated rBMECs expressing familial Alzheimer disease mutation to elucidate how this genetic variant affects barrier properties compared with exposure to oAβ42 (oligomeric amyloid-β [1-42] peptide). RESULTS: Transcriptomic and functional analyses show that rBMECs express a subset of the BBB transcriptome and exhibit stronger paracellular barrier properties, lower caveolar-mediated transport, and comparable PGP (P-glycoprotein) activity compared with primary human BMECs. rBMECs interact with human iPSC-derived pericytes and astrocytes to form a 3D neurovascular system in the MIMETAS microfluidics platform with robust BBB properties. Finally, rBMECs show decreased barrier integrity and upregulation of inflammatory markers. In contrast, treatment of control rBMECs with oAβ42 increases inflammatory markers, but does not alter barrier integrity. CONCLUSIONS: This protocol generates rBMECs with strong BBB properties and a brain-specific transcriptome signature. In addition, the iPSC-derived 3D neurovascular unit system shows some similar properties to the in vivo human BBB. Finally, familial Alzheimer disease mutation alters several BBB-related properties of rBMECs and their inflammatory state, independent of Aβ42 (amyloid-β [1-42] peptide).
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41263083
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Inflammation is a major driver of atherosclerotic cardiovascular disease, and the key roles of trained immunity in initiating and driving this condition are increasingly recognized. However, monitoring trained immunity i...Inflammation is a major driver of atherosclerotic cardiovascular disease, and the key roles of trained immunity in initiating and driving this condition are increasingly recognized. However, monitoring trained immunity in patients, particularly inside the atherosclerotic plaque, remains challenging due to a lack of noninvasive readouts. Here, we discuss the potential of nuclear imaging in studying trained immunity in atherosclerotic cardiovascular disease. We show that many trained immunity-relevant radiotracers exist, including ones targeting innate immune cells, metabolic processes, and epigenetic enzymes. However, their use remains limited, and distinguishing trained immunity from other immune processes remains challenging, highlighting the need for more specific trained immunity biomarkers.
Khan TJ, Meade R, Elizondo-Benedetto S
… +11 more, Belaygorod L, Saffaf O, Rusconi B, Hsu FF, Adak S, Arif B, Zaghloul MS, Li T, Zhang B, Semenkovich CF, Zayed MA
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41263082
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BACKGROUND: is essential for de novo phopholipogenesis and is impacted by diabetes. We previously demonstrated that conditional knockdown of in the endothelium leads to reduced tissue recovery. Therefore, we hypothesiz...BACKGROUND: is essential for de novo phopholipogenesis and is impacted by diabetes. We previously demonstrated that conditional knockdown of in the endothelium leads to reduced tissue recovery. Therefore, we hypothesized that overexpression may also be sufficient in promoting postischemic angiogenesis and recovery in the setting of diabetes. METHODS: CEPT1 (choline-ethanolamine phosphotransferase 1) content was evaluated in the peripheral arteries of human patients with peripheral artery disease and with or without diabetes. We also engineered a conditional endothelial cell (EC)-specific overexpression mouse ( ) in adult C57BL/6J (C57 black 6J) mice and performed unilateral hindlimb ischemia to assess the role of in promoting angiogenesis. Murine aortae and ECs were harvested for single-cell RNA sequencing and molecular pathway analysis. RESULTS: In human arterial intima, CEPT1 was elevated in the setting of peripheral artery disease and diabetes, along with ACOX1 (acyl-coenzyme A oxidase 1), VEGF (vascular endothelial growth factor) R2, p-Akt (phosphorylated Akt), and p-eNOS (phosphorylated endothelial nitric oxide synthase). In mice, single-cell RNA sequencing demonstrated that ECs with overexpression were enriched with wound healing, angiogenesis, sprouting, and cell migration pathways. Diabetic mice that underwent hindlimb ischemia demonstrated improved hindlimb perfusion and angiogenesis, and their aortic rings had increased ex vivo capillary sprouting. overexpression in ECs significantly increased migration, tubule formation, and proliferation as predicted by single-cell RNA sequencing. overexpression in ECs also led to increased expression of , , , and . Similarly, treatment with si and inhibitors for PPARα (peroxisome proliferator-activated receptor α; GW6471), VEGFR2 (ZM323881), Akt (LY294002), and eNOS (L-NAME [nitro-L-arginine methyl ester]) abrogated CEPT1-induced EC migration. CONCLUSIONS: overexpression promotes EC function and postischemic recovery. The impact of CEPT1 on ECs is at least in part dependent on p-Akt/p-eNOS angiogenic signaling and PPARα. Because CEPT1 is elevated in diseased human peripheral arterial tissue, these findings suggest that CEPT1 may be playing an important compensatory role in vascular recovery and reperfusion following ischemic injury in the setting of diabetes.
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41263081
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The plasminogen activation system (PAS) is primarily responsible for the degradation of fibrin clots as well as extracellular matrix remodeling. Many components of the PAS are produced by the liver, and the expression of...The plasminogen activation system (PAS) is primarily responsible for the degradation of fibrin clots as well as extracellular matrix remodeling. Many components of the PAS are produced by the liver, and the expression of these proteins is altered during liver disease. Liver is a primary site for the synthesis of proteins in the PAS, including plasminogen, tPA (tissue-type plasminogen activator), and uPA (urokinase-type plasminogen activator), as well as several modulators of plasmin activation. Clinical studies have shown that liver injury profoundly changes levels of PAS components and fibrinolytic activity in plasma. Likewise, there is strong experimental evidence to suggest that components of the PAS play an important role in determining the severity of hepatic injury and, paradoxically, also contribute to repair and regeneration of the injured liver. Here, we review the dynamic connections between the PAS and liver injury/disease, including changes in PAS expression and function accompanying liver disease in patients and mechanism-centered studies in animal models. We focus on established models of acute hepatic injury, chronic liver disease, and repair/regeneration, and review the effect of gain or loss of function of PAS components on the liver. The review seeks to cover not only field-driving discoveries but also spotlights unexplained dichotomies, challenges with interpretation, and the need for further exploration of mechanisms using leading-edge tools. Critical gaps in our understanding of how the PAS contributes to liver pathophysiology, and vice versa, are identified, and future directions are considered.
Atherosclerosis, a leading cause of cardiovascular diseases, is a chronic, progressive condition driven by lipid dysregulation, endothelial dysfunction, and immune cell infiltration. The PPAR (peroxisome proliferator-act...Atherosclerosis, a leading cause of cardiovascular diseases, is a chronic, progressive condition driven by lipid dysregulation, endothelial dysfunction, and immune cell infiltration. The PPAR (peroxisome proliferator-activated receptor) family of nuclear receptors (PPARα, PPARδ, and PPARγ) is a pivotal regulator of glucose and lipid metabolism, inflammation, and vascular homeostasis. Emerging evidence reveals that PPARs exert complex, context-dependent effects on atherosclerosis that varies by tissue and cell type. This review summarizes the functions and molecular mechanisms of PPARs in the development and treatment of atherosclerosis, focusing on their roles in lipid metabolism, inflammation, and vascular remodeling. We also evaluate the therapeutic potential of PPAR-targeted strategies and highlight critical knowledge gaps for future research.
Sex and reproductive history are established nontraditional risk factors for cardiovascular disease, but their relevance for peripheral artery disease (PAD) remains unclear. This narrative review examines the current evi...Sex and reproductive history are established nontraditional risk factors for cardiovascular disease, but their relevance for peripheral artery disease (PAD) remains unclear. This narrative review examines the current evidence surrounding underlying mechanisms and associations between female sex, reproductive factors, and the development of atherosclerosis, focusing on PAD specifically. Overall, there is a paucity of evidence regarding the association between sex-specific risk factors and PAD. However, hypertensive disorders of pregnancy, gestational diabetes, and adverse pregnancy outcomes are significantly associated with increased incident PAD. Further work is needed to improve the mechanistic understanding of associations between sex-specific risk factors and PAD. In addition, increased clinician awareness may facilitate earlier risk factor detection and preventative strategies. In future, integrating reproductive history into cardiovascular risk assessment may enable more personalized care and ultimately reduce PAD burden among women.
Organ transplantation represents a unique environment in which the donor organ undergoes a systemic insult worsened by procurement that is followed by ischemia-reperfusion injury on revascularization. Historically, micro...Organ transplantation represents a unique environment in which the donor organ undergoes a systemic insult worsened by procurement that is followed by ischemia-reperfusion injury on revascularization. Historically, microvascular thrombosis during sequential injury was considered a cause of organ dysfunction. However, recent data challenge the concept that fibrin deposition in organs drives pathology and instead suggest that the hemostatic system may play an important role in organ recovery. Although fibrin may be protective in the early setting of organ injury, persistent fibrin deposition augments inflammatory leukocyte recruitment that propagates tissue damage. Because the timing of fibrin deposition within the transplanted organ influences both damage and repair, the fibrinolytic system plays an essential role in organ recovery after transplantation. Dysfunctional fibrinolysis is linked to adverse outcomes in many diseases but has received less attention in organ transplantation. This review covers the physiological and pathological role of fibrin formation in liver, kidney, and lung transplantation and discusses how activation of the fibrinolytic system may ultimately modulate outcome.
Zhao H, Chakinala MM, Fallon MB
… +3 more, Lin SM, Lee JS, Dai Z
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41230600
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The lung endothelium is essential for maintaining normal lung structure and plays a key role in gas exchange, barrier function, angiogenesis, vascular tone, and inflammation regulation. The advent of single-cell RNA sequ...The lung endothelium is essential for maintaining normal lung structure and plays a key role in gas exchange, barrier function, angiogenesis, vascular tone, and inflammation regulation. The advent of single-cell RNA sequencing has revealed the unique heterogeneity of pulmonary endothelial cells (ECs) in their function, morphology, and localization. Pulmonary hypertension (PH) is a progressive vascular disorder marked by elevated pulmonary arterial pressure and vascular remodeling. Central to its pathogenesis is EC dysfunction, and emerging evidence highlights EC heterogeneity in driving the complexity of PH. The distinct lung endothelial subpopulations exhibit diverse molecular signatures and functional responses under PH. A complete picture of how these different subpopulations contribute to vascular remodeling of PH is critical to identify novel therapeutic opportunities. This brief review summarizes recent insights into EC dysfunction in PH, focusing on the role of specialized EC subsets and novel therapeutic strategies targeting EC dysfunction. We highlight the integration of cutting-edge technologies in understanding how endothelial heterogeneity shapes the trajectory of PH and opens new avenues for future therapeutic innovations.
Innate immune cells can develop a long-lasting hyperresponsive phenotype by metabolic and epigenetic reprogramming after brief exposure to inflammatory stimuli. Several experimental studies convincingly demonstrated that...Innate immune cells can develop a long-lasting hyperresponsive phenotype by metabolic and epigenetic reprogramming after brief exposure to inflammatory stimuli. Several experimental studies convincingly demonstrated that this immunologic phenomenon, which is called trained immunity, can accelerate the development of atherosclerosis. In this brief review, we summarize current evidence that diets and specific dietary components can modulate trained immunity. In mice, intermittent high-fat diets can reprogram bone marrow myeloid progenitor cells, resulting in hyperinflammatory monocytes and neutrophils that aggravate atherosclerosis. Diet-induced obesity also leads to persistent proinflammatory epigenetic reprogramming of myeloid cells and adipocytes. Hyperglycemia and high-salt diets can also induce trained immunity in murine models. Recent intervention studies in Tanzania revealed that urban Western-style diets trigger systemic inflammation and immune activation, whereas a traditional plant-based heritage diet limits inflammation. Ex vivo studies suggest that this is caused, at least in part, by modulation of trained immunity. Various individual dietary components, such as the flavone apigenin and the polyphenol resveratrol, are able to prevent trained immunity in vitro. It is exciting to speculate how further molecular elucidation on the modulation of trained immunity by diets or isolated dietary components could help to prevent cardiovascular diseases.
Herman AB, Gresova K, Maragkakis M
… +1 more, Autieri MV
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41230598
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Vascular smooth muscle cells (VSMCs) modulate their phenotype from a quiescent, contractile cell to a dedifferentiated, synthetic fibroproliferative cell in response to injury and cardiovascular risk factors. Senescence...Vascular smooth muscle cells (VSMCs) modulate their phenotype from a quiescent, contractile cell to a dedifferentiated, synthetic fibroproliferative cell in response to injury and cardiovascular risk factors. Senescence is a recognized phenotypically distinct cellular state characterized by cell cycle arrest and activation of the p16 and p53 damage response pathway and expression of the senescence-associated secretory phenotype. Low levels of senescence in healthy arteries contribute to vascular homeostasis by ensuring that only healthy VSMCs compose the artery, but they are not intended to be a persistent cellular component of the artery. However, when discussing VSMC phenotype modulation into foam-like cells, macrophages, mesenchymal cells, fibroblasts, adipocytes, and other VSMC-like cells, senescence is rarely included. This raises an intriguing question: can senescence be recognized as a phenotypic state of VSMCs? As understanding SMC phenotypic switching is crucial for developing therapies that can prevent and treat cardiovascular diseases, so is understanding mechanisms of senescence, and targeting the mechanisms that regulate this modulation could be a promising approach for managing conditions such as atherosclerosis, arterial calcification, and aortic aneurysms. This review aims to summarize recent findings about the molecular mechanisms of VSMC senescence and compare similarities and contrasts with the mechanisms known to regulate VSMC phenotype plasticity. Comparison of transcriptomic databases compelled us to also raise the interesting question: if VSMC can regain their contractile phenotype, can they also be coaxed to exit the senescent state and return to the contractile VSMC phenotype? We posit that senescent VSMCs may not be an end point but rather an intermediate or inflection point in VSMC cell fate decision.
Despite a growing therapeutic arsenal, atherosclerotic cardiovascular disease remains the major cause of mortality worldwide. Hepatic lipase, encoded by the gene (lipase C, hepatic type), is a protein that has recently...Despite a growing therapeutic arsenal, atherosclerotic cardiovascular disease remains the major cause of mortality worldwide. Hepatic lipase, encoded by the gene (lipase C, hepatic type), is a protein that has recently regained interest in this context. In this review, we provide a comprehensive overview of the versatile roles of hepatic lipase in lipoprotein metabolism, with a focus on the recently discovered -E97G (point mutation replacing glutamic acid with glycine at position 97) variant. Specifically, we discuss the roles of hepatic lipase in the metabolism of high-density lipoproteins and apoB-containing lipoproteins, as elucidated through in vitro, in vivo, and genetic studies. We also explore the complex interplay between the antiatherogenic and proatherogenic effects of hepatic lipase, highlighting a predominance of antiatherogenic functions for hepatic lipase. Lastly, we briefly discuss how the knowledge on the function of hepatic lipase can potentially be harnessed for the treatment of atherosclerotic cardiovascular disease.
Xue L, Bhattacharya R, Uddin MM
… +27 more, Nakao T, Zou R, Patel A, Haidermota S, Niroula A, Viscosi V, Postupaka D, Bhatnagar A, Finneran P, Bernardo R, Diggs MR, Fitch KV, Chu SM, McCallum S, Currier JS, Fichtenbaum CJ, Malvestutto CD, Aberg JA, Bloomfield GS, Ribaudo HJ, Zanni MV, Libby P, Hornsby W, Lu MT, Douglas PS, Grinspoon SK, Natarajan P
Arterioscler Thromb Vasc Biol
· 2026 Jan · PMID 41195533
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BACKGROUND: People with HIV (PWH) experience higher cardiovascular disease event rates not fully explained by traditional risk factors. Clonal hematopoiesis of indeterminate potential (CHIP), an emerging risk factor for...BACKGROUND: People with HIV (PWH) experience higher cardiovascular disease event rates not fully explained by traditional risk factors. Clonal hematopoiesis of indeterminate potential (CHIP), an emerging risk factor for cardiovascular disease in the general population, has been reported to be more prevalent in PWH. METHODS: Using high-coverage targeted CHIP sequencing in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) cardiovascular disease prevention trial, we investigated whether CHIP increases the risk of major adverse cardiovascular events (MACE) among PWH, as well as whether HIV-associated factors were associated with greater CHIP prevalence among PWH. We analyzed whole-exome and targeted sequencing from 4490 PWH without known cardiovascular disease; 1653 (36.8%) were female, and 2039 (45.4%) were Black. MACE was defined by including cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral artery disease, revascularization, or death from an undetermined cause. RESULTS: A total of 837 (18.6%) had CHIP driver mutations, with 385 (8.6%) at variant allele fraction ≥2% and 61 (1.4%) at variant allele fraction ≥10%. Although overall CHIP was not associated with MACE, the presence of large CHIP (variant allele fraction ≥10%) was associated with increased odds for the first occurrence of myocardial infarction or cardiac catheterization, or revascularization, despite low overall event rates. Adjustments for pitavastatin treatment did not attenuate this association. Furthermore, a larger CHIP clone size was associated with lower CD4 nadir and with increased risk of MACE. CONCLUSIONS: In PWH in the REPRIEVE trial who were low-to-moderate risk for incident cardiovascular disease, CHIP was not associated with increased prospective risk of MACE. However, a large CHIP was associated with increased risk of myocardial infarction and revascularization. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02344290.
Yagi H, Akazawa H, Liu Q
… +12 more, Ito SM, Umei M, Kadowaki H, Matsuoka R, Shindo A, Okamura S, Ueda T, Saga-Kamo A, Ueda K, Takeda N, Takada T, Komuro I
BACKGROUND: Marfan syndrome is an inherited disorder caused by gene mutations, which can lead to thoracic aortic aneurysm and dissection. Selective AT (angiotensin II type 1) receptor blockade is a preventive option aga...BACKGROUND: Marfan syndrome is an inherited disorder caused by gene mutations, which can lead to thoracic aortic aneurysm and dissection. Selective AT (angiotensin II type 1) receptor blockade is a preventive option against Marfan syndrome aortopathy, and recent clinical studies demonstrated that the inhibitory effect of an ARB (AT receptor blocker) losartan on aortic aneurysm growth is equivalent to that of β-blockers. At present, several ARBs are clinically available, and they have drug-specific differences in pharmacological properties. Especially, inverse agonism of ARBs has potential benefits for cardiovascular protection, but its impact on Marfan syndrome aortopathy remains poorly understood. METHODS: Candesartan-7H is a candesartan derivative that lacks the carboxyl group critical for inverse agonist activity and works as a neutral antagonist for the AT receptor. Candesartan cilexetil (1 mg/kg per day), candesartan-7H (1 or 20 mg/kg per day), or vehicle was administered to mice, and aortic dilatation was analyzed using echocardiography, histological staining, and in situ MMP (matrix metalloproteinase) assay. Activation of TGF-β (transforming growth factor β) signaling and mechanosensitive signaling was studied using Western blot and immunohistochemical analysis. RESULTS: Candesartan cilexetil (1 mg/kg per day) and candesartan-7H (20 mg/kg per day) lowered blood pressures equally in mice. Progressive dilatation of the aorta in association with aortic wall thickening, degeneration of elastic fibers, deposition of collagen, MMP activation, and TGF-β signaling activation in mice was significantly suppressed by treatment with candesartan cilexetil (1 mg/kg per day), but not by candesartan-7H, even at 20 mg/kg per day. In addition, candesartan cilexetil, but not candesartan-7H, suppressed activation of mechanosensitive signaling involving focal adhesion kinase, p38 mitogen-activated protein kinase, and early growth response-1 in the ascending aorta of mice. CONCLUSIONS: Our findings support a crucial role of inverse agonist activity of ARB for the prevention of mechanical stress-induced AT receptor activation and aortic aneurysm progression in Marfan syndrome mice.