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Angiogenesis is regulated in coordinated fashion by chemical and mechanical cues acting on endothelial cells (ECs). However, the mechanobiological mechanisms of angiogenesis remain unknown. Herein, we demonstrate a crucial role of blood flow-driven intraluminal pressure (IP) in regulating wound angiogenesis. During wound angiogenesis, blood flow-driven IP loading inhibits elongation of injured blood vessels located at sites upstream from blood flow, while downstream injured vessels actively elongate. In downstream injured vessels, F-BAR proteins, TOCA1 and CIP4, localize at leading edge of ECs to promote N-WASP-dependent Arp2/3 complex-mediated actin polymerization and front-rear polarization for vessel elongation. In contrast, IP loading expands upstream injured vessels and stretches ECs, preventing leading edge localization of TOCA1 and CIP4 to inhibit directed EC migration and vessel elongation. These data indicate that the TOCA family of F-BAR proteins are key actin regulatory proteins required for directed EC migration and sense mechanical cell stretching to regulate wound angiogenesis. Chemical and mechanical cues coordinately regulate angiogenesis. Here, the authors show that blood flow-driven intraluminal pressure regulates wound angiogenesis. Findings indicate that TOCA family of F-BAR proteins act as actin regulators required for endothelial cell migration and sense mechanical cell stretching to regulate wound angiogenesis.

The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E2 (PGE2). Although inhibition of 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) is reported to lead to PGE2 accumulation, the role of 15‐PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild‐type and 15‐pgdh+/− mice and found that 15‐pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer‐associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15‐pgdh+/− mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15‐pgdh+/−Acta2‐TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15‐pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion. Depletion of 15‐PGDH remodelling tumor microenvironment by promoting firosis and angiogenesis via the upregulation of FGF1 and VEGF.

Genetic mutations in the isocitrate dehydrogenase (IDH) gene that result in a pathological enzymatic activity to produce oncometabolite have been detected in acute myeloid leukemia (AML) patients. While specific inhibitors that target mutant IDH enzymes and normalize intracellular oncometabolite level have been developed, refractoriness and resistance has been reported. Since acquisition of pathological enzymatic activity is accompanied by the abrogation of the crucial WT IDH enzymatic activity in IDH mutant cells, aberrant metabolism in IDH mutant cells can potentially persist even after the normalization of intracellular oncometabolite level. Comparisons of isogenic AML cell lines with and without IDH2 gene mutations revealed two mutually exclusive signalings for growth advantage of IDH2 mutant cells, STAT phosphorylation associated with intracellular oncometabolite level and phospholipid metabolic adaptation. The latter came to light after the oncometabolite normalization and increased the resistance of IDH2 mutant cells to arachidonic acid‐mediated apoptosis. The release of this metabolic adaptation by FDA‐approved anti‐inflammatory drugs targeting the metabolism of arachidonic acid could sensitize IDH2 mutant cells to apoptosis, resulting in their eradication in vitro and in vivo. Our findings will contribute to the development of alternative therapeutic options for IDH2 mutant AML patients who do not tolerate currently available therapies. Phospholipid metabolic adaptation in IDH2 mutant acute myeloid leukemia (AML) cells underlies their resistance to apoptosis. Food and Drug Administration‐approved anti‐inflammatory drugs targeting the metabolism of arachidonic acid can sensitize IDH2 mutant AML cells to apoptosis.

Atrial fibrillation (AF) and heart failure (HF) contribute to about 45% of all cardiovascular disease (CVD) deaths in the USA and around the globe. Due to the complex nature, progression, inherent genetic makeup, and heterogeneity of CVDs, personalized treatments are believed to be critical. To improve the deciphering of CVD mechanisms, we need to deeply investigate well-known and identify novel genes that are responsible for CVD development. With the advancements in sequencing technologies, genomic data have been generated at an unprecedented pace to foster translational research. Correct application of bioinformatics using genomic data holds the potential to reveal the genetic underpinnings of various health conditions. It can help in the identification of causal variants for AF, HF, and other CVDs by moving beyond the one-gene one-disease model through the integration of common and rare variant association, the expressed genome, and characterization of comorbidities and phenotypic traits derived from the clinical information. In this study, we examined and discussed variable genomic approaches investigating genes associated with AF, HF, and other CVDs. We collected, reviewed, and compared high-quality scientific literature published between 2009 and 2022 and accessible through PubMed/NCBI. While selecting relevant literature, we mainly focused on identifying genomic approaches involving the integration of genomic data; analysis of common and rare genetic variants; metadata and phenotypic details; and multi-ethnic studies including individuals from ethnic minorities, and European, Asian, and American ancestries. We found 190 genes associated with AF and 26 genes linked to HF. Seven genes had implications in both AF and HF, which are SYNPO2L, TTN, MTSS1, SCN5A, PITX2, KLHL3 , and AGAP5 . We listed our conclusion, which include detailed information about genes and SNPs associated with AF and HF.

Coronary arteries are a critical part of the vascular system and provide nourishment to the heart. In humans, even minor defects in coronary arteries can be lethal, emphasizing their importance for survival. However, some teleosts survive without coronary arteries, suggesting that there may have been some evolutionary changes in the morphology and function of coronary arteries in the tetrapod lineage. Here, we propose that the true ventricular coronary arteries were newly established during amniote evolution through remodeling of the ancestral coronary vasculature. In mouse ( Mus musculus ) and Japanese quail ( Coturnix japonica ) embryos, the coronary arteries unique to amniotes are established by the reconstitution of transient vascular plexuses: aortic subepicardial vessels (ASVs) in the outflow tract and the primitive coronary plexus on the ventricle. In contrast, amphibians ( Hyla japonica , Lithobates catesbeianus , Xenopus laevis , and Cynops pyrrhogaster ) retain the ASV-like vasculature as truncal coronary arteries throughout their lives and have no primitive coronary plexus. The anatomy and development of zebrafish ( Danio rerio ) and chondrichthyans suggest that their hypobranchial arteries are ASV-like structures serving as the root of the coronary vasculature throughout their lives. Thus, the ventricular coronary artery of adult amniotes is a novel structure that has acquired a new remodeling process, while the ASVs, which occur transiently during embryonic development, are remnants of the ancestral coronary vessels. This evolutionary change may be related to the modification of branchial arteries, indicating considerable morphological changes underlying the physiological transition during amniote evolution. Coronary arteries are tasked with supplying the heart with oxygenated blood and nutrients. Any blockage or developmental problem in these blood vessels can have severe and sometimes lethal consequences. Due to their importance for health, researchers have extensively studied how coronary arteries form in humans and mice; a more limited range of studies have also looked at their equivalent in zebrafish. However, little is known about these structures develop in animals such as birds, amphibians, or other groups of fish. This makes it difficult to retrace the evolutionary processes that have given rise to the coronary arteries we are familiar with in mammals. To address this knowledge gap, Mizukami et al. set out to compare blood vessel development around the heart of mammals, birds, amphibians, and fish. To do this, they performed detailed anatomical studies of blood vessel structure at different stages of development in mice as well as quail, frogs and newts, zebrafish and sharks. In both mice and quail, small arterial subepicardial vessels (or ASVs) emerged early in development around the heart; these subsequently reorganised and remodelled themselves to give rise to the ‘true’ coronary arteries characteristic of the mature heart. Frogs and newts also developed similar ASV-like structures; however, unlike their mammalian and bird equivalents, these vessels did not reorganise, instead being retained into adulthood. In fish, blood vessel development resembled that of amphibians, suggesting that the coronary artery-like structures seen in some fish are an ‘ancestral’ form of ASVs, rather than the equivalent of the mature coronary arteries in mammals and birds. This work sheds light on the evolutionary processes shaping essential structures in the heart. In the future, Mizukami et al. hope that this knowledge will help develop a greater range of experimental animal models for studying heart disease and potential treatments.

Sprouting angiogenesis is a form of morphogenesis which expands vascular networks from preexisting networks. However, the precise mechanism governing efficient branch elongation driven by directional movement of endothelial cells (ECs), while the lumen develops under the influence of blood inflow, remains unknown. Herein, we show perivascular stiffening to be a major factor that integrates branch elongation and lumen development. The lumen expansion seen during lumen development inhibits directional EC movement driving branch elongation. This process is counter-regulated by the presence of pericytes, which induces perivascular stiffening by promoting the deposition of EC-derived collagen-IV (Col-IV) on the vascular basement membrane (VBM), thereby preventing excessive lumen expansion. Furthermore, inhibition of forward directional movement of the tip EC during lumen development is associated with decreased localization of the F-BAR proteins and Arp2/3 complexes at the leading front. Our results demonstrate how ECs elongate branches, while the lumen develops, by properly building the surrounding physical environment in coordination with pericytes during angiogenesis. During angiogenesis, a new branch elongates while the lumen develops. Here, the authors show that perivascular stiffening integrates branch elongation and lumen development to allow angiogenesis to proceed properly while exposed to blood flow.

BackgroundAlthough sarcopenic obesity is associated with a higher risk of cardiovascular events compared with obesity without sarcopenia, it is difficult to diagnose sarcopenia in daily clinical settings. Recently, a simple scoring system has been developed to identify sarcopenia patients based on three variables (age, hand grip strength, and calf circumference). However, the utility of this score for cardiovascular risk stratification in patients with abdominal obesity is unknown.MethodsWe calculated the sarcopenia score in 262 patients with abdominal obesity, defined as a waist circumference ≥90 cm in women or ≥85 cm in men. The composite endpoint of this study was cardiovascular mortality, nonfatal myocardial infarction, stroke, unstable angina, and heart failure hospitalization.ResultsOf the 262 patients, 108 had a high sarcopenia score based on previously established criteria (≥105 in men and ≥120 in women). The patients with a high sarcopenia score had a significantly higher plasma level of B-type natriuretic peptide compared with those with a low sarcopenia score (median 56.7, interquartile range [28.2–142.9] vs. 37.9 [13.8–76.1] pg/mL; p < 0.0001). Kaplan–Meier curves revealed a significantly lower event-free survival rate in those with a high compared with a low sarcopenia score (log-rank test p = 0.001), even after adjustment for confounding factors using propensity score matching (log-rank test p = 0.009). Multivariate Cox proportional hazard analysis identified a high sarcopenia score (hazard ratio: 2.46; 95% confidence interval: 1.31–4.64, p = 0.005) as an independent predictor of the primary endpoints. The combination of a high sarcopenia score and low body mass index (<25 kg/m2) predicted a significantly higher risk of future adverse events (p = 0.005). Furthermore, patients with a high sarcopenia score and high B-type natriuretic peptide level (≥200 pg/mL) had the poorest prognosis (p < 0.0001).ConclusionsThis simple screening test for sarcopenia can predict future adverse cardiovascular events in patients with abdominal obesity.

Little is known about the significance of asymptomatic intra-cranial lesions (ICL) identified by brain MRI in coronary artery disease (CAD) patients. Silent cerebral lesions are suggested to be associated with arterial stiffness in healthy subjects. We investigated whether subclinical ICL are associated with arterial stiffness and the prognosis in CAD patients without medical history of cerebrovascular diseases. We recruited CAD patients who required percutaneous coronary intervention (PCI), did not meet exclusion criteria, and agreed with MRI before PCI. Subjects were divided into two groups according to the presence of ICL of cerebral microbleeds or lacunar infarction. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). Clinical outcome was defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke, unstable angina and heart failure. In total, 149 patients underwent brain MRI. Patients with ICL (n=55) had significantly higher baPWV than those without ICL (1591-2204 vs. 1450-1956 cm per sec; P=0.009). A multivariate analysis showed that male sex (odds ratio (OR), 3.15; 95% confidence interval (CI), 1.38-7.20; P=0.006) and baPWV (OR, 1.001; 95% CI, 1.000-1.002; P=0.023) were predictors of ICL. In total, 12 patients experienced a cardiovascular event. The Kaplan-Meier analysis indicated a significantly higher incidence of cardiovascular events in patients with ICL (log-rank test: P=0.018). Multivariate Cox proportional hazards analyses indicated that ICL finding was a significant predictor of clinical outcome (hazard ratio, 3.41; 95% CI, 1.02-11.5; P=0.047). Patients with subclinical ICL had a higher baPWV and worse prognoses than those without ICL.

Aims The focus on wild‐type transthyretin amyloid cardiomyopathy (ATTRwt‐CM) is increasing because of novel treatment options. There is currently no report on a large number of Japanese patients with ATTRwt‐CM. The study aimed to examine the characteristics and prognosis of ATTRwt‐CM in Japan. Methods and results Consecutive patients (78.5 ± 6.4 years old at diagnosis) with ATTRwt‐CM diagnosed at Kumamoto University Hospital between December 2002 and December 2019 were retrospectively reviewed. Data, including demographic characteristics, co‐morbidities, clinical manifestations at diagnosis, laboratory results, electrocardiographic and echocardiographic data, imaging and pathological findings, and treatment were obtained. Of 129 patients included in this study, 110 patients (85%) were male. The median period from initial symptom onset to diagnosis was 15.5 (2–75) months. Heart failure was the most common clinical manifestation leading to diagnosis (61%) and initial manifestations (49%). Of 106 patients, carpal tunnel syndrome was observed in 57 patients (54%), and the median period from initial symptom onset to diagnosis was 96 (48–120) months. Histopathological confirmation of transthyretin amyloid was achieved in 94 patients (73%), including 66 (51%) and 28 cases (22%) with endomyocardial and extracardiac biopsies. During the observation period (median 15.0 [inter‐quartile range, 5.4–33.2] months after diagnosis), 34 patients (26%) died. Of these, 27 patients (79%) had cardiovascular deaths (heart failure, 25; sudden death, two). The median survival duration was 58.9 months and the 5 years' survival rate was 48%. According to a multivariate Cox hazard analysis, age [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05–1.23, P = 0.002] and low serum sodium levels (HR, 0.89; 95% CI, 0.79–0.996; P = 0.04) contributed to all‐cause mortality, and low serum sodium levels contributed to hospitalization for heart failure (HR, 0.86; 95% CI, 0.77–0.96; P = 0.005). Conclusions Clinical characteristics and prognosis of ATTRwt‐CM patients in Japan were examined. Carpal tunnel syndrome can be considered an indication for diagnosis of ATTRwt‐CM. Age and low serum sodium level were significant predictive factors of all survival outcomes. The clinical features of ATTRwt‐CM should be recognized to provide appropriate treatment.