Vascular Development Research Articles

Postnatal cytomegalovirus infection and pulmonary vascular disease in extremely premature infants: A case series.

Pulmonary vascular disease (PVD) is a major determinant of both morbidity and mortality in extremely low birth weight infants. It is biologically plausible that postnatal cytomegalovirus (pCMV) infection may lead to PVD in premature infants secondary to pneumonitis or via derangement of pulmonary vascular development directly through endothelial dysfunction. Uncertainty remains, however, regarding thresholds for intervention in premature infants with cardiorespiratory instability and presumed CMV infection likely secondary to the limited understanding of the natural history of the disease. We describe four cases of premature infants with clinical and echocardiography features of PVD, in the setting of postnatally acquired CMV. All patients had atypical PVD trajectories, refractory to vasodilator treatment, which improved after initiation of CMV treatment. We highlight the need to consider postnatally acquired CMV infection in patients with PVD non-responsive to standard pulmonary vasodilator therapies or disease severity which is out of proportion of the usual clinical trajectory. Treatment of extremely premature infants with CMV-associated PVD may have positive impact on cardiorespiratory health, although duration of therapy remains uncertain.

Origin and flow-mediated remodeling of the murine and human extraembryonic circulation systems.

The transduction of mechanical stimuli produced by blood flow is an important regulator of vascular development. The vitelline and umbilico-placental circulations are extraembryonic vascular systems that are required for proper embryonic development in mammalian embryos. The morphogenesis of the extraembryonic vasculature and the cardiovascular system of the embryo are hemodynamically and molecularly connected. Here we provide an overview of the establishment of the murine and human vitelline and umbilico-placental vascular systems and how blood flow influences various steps in their development. A deeper comprehension of extraembryonic vessel development may aid the establishment of stem-cell based embryo models and provide novel insights to understanding pregnancy complications related to the umbilical cord and placenta.

Rhamnogalacturonan lyase 1 (RGL1), as a suppressor of E3 ubiquitin ligase Arabidopsis thaliana ring zinc finger 1 (AtRZF1), is involved in dehydration response to mediate proline synthesis and pectin rhamnogalacturonan-I composition.

Proline metabolism plays a crucial role in both environmental stress responses and plant growth. However, the specific mechanism by which proline contributes to abiotic stress processes remains to be elucidated. In this study, we utilized atrzf1 (Arabidopsis thaliana ring zinc finger 1) as a parental line for T-DNA tagging mutagenesis and identified a suppressor mutant of atrzf1, designated proline content alterative 31 (pca31). The pca31 mutant suppressed the insensitivity of atrzf1 to dehydration stress during early seedling growth. Using Thermal Asymmetric Interlaced-PCR, we found that the T-DNA of pca31 was inserted into the promoter region of the At2g22620 gene, which encodes the cell wall enzyme rhamnogalacturonan lyase 1 (RGL1). Enzymatic assays indicated that RGL1 exhibited rhamnogalacturonan lyase activity, influencing cell wall pectin composition. The decrease in RGL1 gene expression suppressed the transcriptomic perturbation of the atrzf1 mutant. Silencing of the RGL1 gene in atrzf1 resulted in a sensitive phenotype similar to pca31 under osmotic stress conditions. Treatment with mannitol, salt, hydrogen peroxide, and abscisic acid induced RGL1 expression. Furthermore, we uncovered that RGL1 plays a role in modulating root growth and vascular tissue development. Molecular, physiological, and genetic experiments revealed that the positive modulation of RGL1 during abiotic stress was linked to the AtRZF1 pathway. Taken together, these findings establish that pca31 acts as a suppressor of atrzf1 in abiotic stress responses through proline and cell wall metabolisms.

Exosomes: A New Hope for Angiogenesis-Mediated Bone Regeneration.

Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions. After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future.

Single-cell transcriptome profiling reveals the spatiotemporal distribution of triterpenoid saponin biosynthesis and transposable element activity in Gynostemma pentaphyllum shoot apexes and leaves.

Gynostemma pentaphyllum (Thunb.) Makino is an important producer of dammarene-type triterpenoid saponins. These saponins (gypenosides) exhibit diverse pharmacological benefits such as anticancer, antidiabetic, and immunomodulatory effects, and have major potential in the pharmaceutical and health care industries. Here, we employed single-cell RNA sequencing (scRNA-seq) to profile the transcriptomes of more than 50,000 cells derived from G. pentaphyllum shoot apexes and leaves. Following cell clustering and annotation, we identified five major cell types in shoot apexes and four in leaves. Each cell type displayed substantial transcriptomic heterogeneity both within and between tissues. Examining gene expression patterns across various cell types revealed that gypenoside biosynthesis predominantly occurred in mesophyll cells, with heightened activity observed in shoot apexes compared to leaves. Furthermore, we explored the impact of transposable elements (TEs) on G. pentaphyllum transcriptomic landscapes. Our findings the highlighted the unbalanced expression of certain TE families across different cell types in shoot apexes and leaves, marking the first investigation of TE expression at the single-cell level in plants. Additionally, we observed dynamic expression of genes involved in gypenoside biosynthesis and specific TE families during epidermal and vascular cell development. The involvement of TE expression in regulating cell differentiation and gypenoside biosynthesis warrant further exploration. Overall, this study not only provides new insights into the spatiotemporal organization of gypenoside biosynthesis and TE activity in G. pentaphyllum shoot apexes and leaves but also offers valuable cellular and genetic resources for a deeper understanding of developmental and physiological processes at single-cell resolution in this species.

Pharmacological control of angiogenesis by regulating phosphorylation of myosin light chain 2

BackgroundControl of angiogenesis is widely considered a therapeutic strategy, but reliable control methods are still under development. Phosphorylation of myosin light chain 2 (MLC2), which regulates actin-myosin interaction, is critical to the behavior of vascular endothelial cells (ECs) during angiogenesis. MLC2 is phosphorylated by MLC kinase (MLCK) and dephosphorylated by MLC phosphatase (MLCP) containing a catalytic subunit PP1. We investigated the potential role of MLC2 in the pharmacological control of angiogenesis. Methods and resultsWe exposed transgenic zebrafish Tg(fli1a:Myr-mCherry)ncv1 embryos to chemical inhibitors and observed vascular development. PP1 inhibition by tautomycetin increased length of intersegmental vessels (ISVs), whereas MLCK inhibition by ML7 decreased it; these effects were not accompanied by structural dysplasia. ROCK inhibition by Y-27632 also decreased vessel length. An in vitro angiogenesis model of human umbilical vein endothelial cells (HUVECs) showed that tautomycetin increased vascular cord formation, whereas ML7 and Y-27632 decreased it. These effects appear to be influenced by regulation of cell morphology rather than cell viability or motility. Actin co-localized with phosphorylated MLC2 (pMLC2) was abundant in vascular-like elongated-shaped ECs, but poor in non-elongated ECs. pMLC2 was associated with tightly arranged actin, but not with loosely arranged actin. Moreover, knockdown of MYL9 gene encoding MLC2 reduced total MLC2 and pMLC2 protein and inhibited angiogenesis in HUVECs. ConclusionThe present study found that MLC2 is a pivotal regulator of angiogenesis. MLC2 phosphorylation may be involved in the regulation of of cell morphogenesis and cell elongation. The functionally opposite inhibitors positively or negatively control angiogenesis, probably through the regulating EC morphology. These findings may provide a unique therapeutic target for angiogenesis.

Low shear stress-induced blockage of autophagic flux impairs endothelial barrier and facilitates atherosclerosis in mice

Atherosclerosis preferentially occurs in areas with low shear stress (LSS) and oscillatory flow. LSS has been demonstrated to correlate with the development of atherosclerosis. The sphingosine 1-phosphate receptor 1 (S1PR1), involving intravascular blood flow sensing, regulates vascular development and vascular barrier function. However, whether LSS affects atherosclerosis via regulating S1PR1 remains incompletely clear. In this study, immunostaining results of F-actin, β-catenin, and VE-cadherin indicated that LSS impaired endothelial barrier function in human umbilical vein endothelial cells (HUVECs). Western blot analysis showed that LSS resulted in blockage of autophagic flux in HUVECs. In addition, autophagy agonist Rapamycin (Rapa) antagonized LSS-induced endothelial barrier dysfunction, whereas autophagic flux inhibitor Bafilomycin A1 (BafA1) exacerbated it, indicating that LSS promoted endothelial barrier dysfunction by triggering autophagic flux blockage. Notably, gene expression analysis revealed that LSS downregulated S1PR1 expression, which was antagonized by Rapa. Selective S1PR1 antagonist W146 impaired endothelial barrier function of HUVECs under high shear stress (HSS) conditions. Moreover, our data showed that expression of GAPARAPL2, a member of autophagy-related gene 8 (Atg8) proteins, was decreased in HUVECs under LSS conditions. Autophagic flux blockage induced by GAPARAPL2 knockdown inhibited S1PR1, aggravated endothelial barrier dysfunction of HUVECs in vitro, and promoted aortic atherosclerosis in ApoE−/− mice in vivo. Our study demonstrates that autophagic flux blockage induced by LSS downregulates S1PR1 expression and impairs endothelial barrier function. GABARAPL2 inhibition is involved in LSS-induced autophagic flux blockage, which impairs endothelial barrier function via downregulation of S1PR1.

Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function.

Zinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specific Zmiz1 knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling of ZMIZ1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migration in vitro. We also presented evidence that Zmiz1 regulates Prox1 expression in vitro and in vivo by modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss of Zmiz1 in mesenteric lymphatic vessels significantly reduced valve density. Collectively, our results highlight a novel role of Zmiz1 in LECs and as a transcriptional regulator of Prox1, shedding light on a previously unknown regulatory factor in lymphatic vascular biology.

Disruption of maternal vascular remodeling by a fetal endoretrovirus-derived gene in preeclampsia

BackgroundPreeclampsia, one of the most lethal pregnancy-related diseases, is associated with the disruption of uterine spiral artery remodeling during placentation. However, the early molecular events leading to preeclampsia remain unknown.ResultsBy analyzing placentas from preeclampsia, non-preeclampsia, and twin pregnancies with selective intrauterine growth restriction, we show that the pathogenesis of preeclampsia is attributed to immature trophoblast and maldeveloped endothelial cells. Delayed epigenetic reprogramming during early extraembryonic tissue development leads to generation of excessive immature trophoblast cells. We find reduction of de novo DNA methylation in these trophoblast cells results in selective overexpression of maternally imprinted genes, including the endoretrovirus-derived gene PEG10 (paternally expressed gene 10). PEG10 forms virus-like particles, which are transferred from the trophoblast to the closely proximate endothelial cells. In normal pregnancy, only a low amount of PEG10 is transferred to maternal cells; however, in preeclampsia, excessive PEG10 disrupts maternal vascular development by inhibiting TGF-beta signaling.ConclusionsOur study reveals the intricate epigenetic mechanisms that regulate trans-generational genetic conflict and ultimately ensure proper maternal–fetal interface formation.

The mechanism of Xihuang pills' intervention in the tumour immune microenvironment for the treatment of liver cancer based on the STAT3-PDL1 pathway

Ethnopharmacological relevanceXihuang pills, a time-honored Chinese compound formula with a history spanning thousands of years, have demonstrated remarkable efficacy in treating various cancers, such as breast cancer, colon cancer, and liver cancer. Clinical applications over the years have established their effectiveness. Several scholars conducting experimental studies have elucidated the potent tumor-suppressing effects of Xihuang pills. While the inhibition of tumor vascular development and prevention of tumor cell invasion and metastasis have been well-explored mechanisms, the impact on the tumor immune microenvironment has received less attention. This study focuses on investigating the immune microenvironment adjustments induced by Xihuang pills in hepatocellular carcinoma. Aim of the studyTumour cells will find an escape phenomenon during tumour immunotherapy, which will affect immunotherapy results. We will research the regulation of the tumour immune microenvironment, to provide a more complete and precise basis for the elucidation of the mechanism of Xihuang pills in treating cancers. It provides new research ideas for people to treat liver cancer. Materials and methodsThrough in vivo and in vitro assessments confirming the intervention effects of Xihuang pills, we observed alterations in T cell typing, macrophage polarization, and tumor-associated cytokine levels. The primary active ingredients of Xihuang pills were identified using UPLC-MS/GC-MS, and relevant pathways in the treatment of hepatocellular carcinoma were predicted through network pharmacology. Combining the network pharmacology approach, we predicted the pathways relevant to Xihuang pills in treating hepatocellular carcinoma and experimentally validated the involvement of PD-1/PD-L1, a key immunity-related axis. ResultsXihuang Pill has a regulatory effect on the tumor immune microenvironment. ConclusionsThe results indicated that Xihuang pills could impact splenic lymphocyte phenotyping, macrophage polarization, and IL-6 cytokine expression in liver cancer mice. The mechanism of action was associated with the regulation of the PD-1/PD-L1 signaling pathway by the STAT3 protein.

Abstract 1129: Ddx24 In Vascular Smooth Muscle Cells Is Essential For Embryonic Vascular Development

Background: The DEAD-box family plays a crucial role in tumorigenesis and immune responses. Our previous research has identified an association between the dysfunction of DEAD-box RNA helicase 24 (DDX24) and a specific type of vascular malformation. However, the role and mechanism of DDX24 in vascular development remains unclear.Research questions: What is the role of DDX24 in regulating vascular smooth muscle cell (VSMC) function and embryonic vascular development? Aims: Our aim is to investigate the function and regulatory mechanism of DDX24 in embryonic vascular development. Methods: Cardiomyocyte/VSMC-specific Ddx24 knockout mice were generated by crossing Tagln -Cre mice with Ddx24 flox/flox transgenic mice. Stereomicroscopic photography and immunofluorescence staining were used to examine the development of blood vessels. Flow cytometry and cell proliferation assays were employed to assess the effect of DDX24 on VSMC functions. RNA sequencing and RNA immunoprecipitation were performed to uncover the downstream target of DDX24. Additionally, RNA pull-down and RNA stability experiments were conducted to elucidate the regulatory mechanism. Results: Cardiomyocyte/VSMC-specific Ddx24 knockout mice died before embryonic day 13.5 and exhibited defects in embryonic vascular formation and vascular remodeling in extraembryonic tissues. Ddx24 knockdown led to the suppression of VSMC proliferation through cell cycle arrest, likely due to increased DNA damage. DDX24 protein was found to bind to and stabilize the mRNA of FA complementation group A ( FANCA ), a gene that responds to DNA damage. Depletion of FANCA also affected cell cycle and DNA repair in VSMCs. Overexpression of FANCA successfully rescued the alterations induced by DDX24 deficiency. Conclusion: Our study illuminates the role of DDX24 in VSMC-mediated vascular development, suggesting a potential therapeutic target for diseases associated with VSMC dysfunction.

Abstract 1039: Endothelial Deletion Of Nck1 Reduces Atherosclerosis In Apoe-/- Mice Through The Nck1-atf3 Axis

The Nck family of signaling adaptors, including both Nck1 and Nck2, classically regulate cell motility during vascular development and postnatal angiogenesis. While Nck1 and Nck2 play redundant roles in this regard with deletion of both isoforms required to affect tissue remodeling, we demonstrated that global Nck1 deletion was sufficient to reduce atherosclerotic plaque formation and selective Nck1 inhibition reduces proinflammatory endothelial activation in response to oscillatory shear stress. Therefore, we sought to determine the role of endothelial Nck1 in atherosclerosis and ischemic angiogenesis using novel endothelial-specific Nck1 knockout mice. Endothelial-specific Nck1 deletion significantly reduced Western diet-induced atherosclerotic plaque formation at multiple sites compared to mice expressing endothelial-specific Cre alone or to endothelial-specific Nck2 knockout mice. This reduced plaque formation was characterized by diminished macrophage and smooth muscle incorporation despite enhanced weight gain in endothelial Nck1 knockout mice. RNA Sequencing analysis of endothelial cells in culture showed that Nck1 depletion reduces the expression of a variety of proinflammatory pathways but enhances the expression of genes involved in central carbon metabolism and proliferation. While Nck1 deletion is sufficient to blunt atherogenic inflammation, Nck1 inhibition did not affect angiogenesis or limb perfusion in the femoral artery ligation model of hind limb ischemia. To further characterized Nck1’s proinflammatory role, we utilized affinity precipitation-mass spectrometry and identified Activating Transcription Factor 3 ATF3 as a Nck1-selective binding partner. While no studies to date have examined endothelial ATF3 signaling in atherosclerosis, our preliminary data show that Nck1 is required for ATF3 expression in response to disturbed flow in vitro and in vivo , but the mechanism by which disturbed flow stimulates ATF3 expression remains unknown. ATF3 knockdown reduces disturbed flow-induced proinflammatory gene expression, suggesting that the Nck1-ATF3 signaling axis is a novel regulator of flow-induced inflammation.

Identification of novel SNPs and candidate genes significantly affecting growth in grass carp (Ctenopharyngodon idella) through GWAS analysis

Grass carp (Ctenopharyngodon idella) is one of the most important cultivated fish species in the global freshwater aquaculture with fast growth, low cost of production and delicious meat. A breeding program to improve economically important growth traits in grass carp would benefit from effective molecular markers. Although a genetic linkage map of grass carp has been constructed, and quantitative trait loci (QTL) mapping and a genome-wide association study (GWAS) have been conducted, the effective number of SNP markers and genes currently available for breeding is still very limited. In this study, we conducted a GWAS based on re-sequencing of individuals to identify genomic regions and candidate genes potentially associated with various growth traits of grass carp, including body weight (BW), body length (BL) and body height (BH). A total of 4,854,366 high-quality SNPs were identified and located on 24 chromosomes. Among them, 31 SNPs were identified as being associated with growth traits, including 8 SNPs on chromosomes 1, 2, 10, 13, 14, 17 and 22 associated with BW, 21 SNPs on chromosomes 2, 4, 5, 8, 10, 13, 14, 15, 17, 23 and 24 correlated with BL, and 18 SNPs on chromosomes 2, 9, 10, 13, 14, 17, 23 and 24 related to BH. In addition, 13 of these SNPs were simultaneously associated with two or three growth traits. Within a 48 kb range upstream and downstream of these significant SNPs, 120 candidate genes were identified to be associated with the QTLs. Most of these genes were related to growth and development, fat metabolism, bone mineralization and differentiation, vascular development, and feeding regulation. Notably, the genes pwp1, cers5, chrebp, lsr, ctnnbip1, smoc2, ano6 and cckrb were specifically associated with growth, fat, bone formation and feeding. Our findings would provide a foundation for molecular marker-assisted selection, genomic selection, and functional analysis of growth traits in grass carp.

Placental exosomes in pregnancy and preeclampsia.

Preeclampsia, poses significant risks to both maternal and fetal well-being. Exosomes released by the placenta play a crucial role in intercellular communication and are recognized as potential carriers of essential information for placental development. These exosomes transport a payload of proteins, nucleic acids, and lipids that mirror the placental microenvironment. This review delves into the functional roles of placental exosomes and its contents shedding light on their involvement in vascular regulation and immune modulation in normal pregnancy. Discernible changes are reported in the composition and quantity of placental exosome contents in pregnancies affected by preeclampsia. The exosomes from preeclamptic mothers affect vascularization and fetal kidney development. The discussion also explores the implications of utilizing placental exosomes as biomarkers and the prospects of translating these findings into clinical applications. In conclusion, placental exosomes hold promise as a valuable avenue for deciphering the complexities of preeclampsia, providing crucial diagnostic and prognostic insights. As the field progresses, a more profound comprehension of the distinct molecular signatures carried by placental exosomes may open doors to innovative strategies for managing and offering personalized care to pregnancies affected by preeclampsia.

Transcriptome analysis of cardiac endothelial cells after myocardial infarction reveals temporal changes and long-term deficits.

Endothelial cells (ECs) have essential roles in cardiac tissue repair after myocardial infarction (MI). To establish stage-specific and long-term effects of the ischemic injury on cardiac ECs, we analyzed their transcriptome at landmark time points after MI in mice. We found that early EC response at Day 2 post-MI centered on metabolic changes, acquisition of proinflammatory phenotypes, initiation of the S phase of cell cycle, and activation of stress-response pathways, followed by progression to mitosis (M/G2 phase) and acquisition of proangiogenic and mesenchymal properties during scar formation at Day 7. In contrast, genes involved in vascular physiology and maintenance of vascular tone were suppressed. Importantly, ECs did not return to pre-injury phenotypes after repair has been completed but maintained inflammatory, fibrotic and thrombotic characteristics and lost circadian rhythmicity. We discovered that the highest induced transcript is the mammalian-specific Sh2d5 gene that promoted migration and invasion of ECs through Rac1 GTPase. Our results revealed a synchronized, temporal activation of disease phenotypes, metabolic pathways, and proliferation in quiescent ECs after MI, indicating that precisely-timed interventions are necessary to optimize cardiac tissue repair and improve outcomes. Furthermore, long-term effects of acute ischemic injury on ECs may contribute to vascular dysfunction and development of heart failure.

Chronic Gestational Hypoxia Alters Plasma Exosomal miRNA Profile and Pulmonary Arterial Proteome and Metabolome in Fetal Lambs

Antenatal chronic hypoxia negatively impacts fetal development and increases the risk of cardio-pulmonary dysfunction after birth, including newborn pulmonary hypertension. Previously, we showed that fetal and newborn sheep exposed to chronic hypoxia during gestation exhibit a variety of cardio-pulmonary defects that parallel those of human infants including pulmonary vascular remodeling, heart dysfunction, and pulmonary hypertension. To explore the mechanisms involved in hypoxia-mediated newborn pulmonary hypertension, we test the hypothesis that antenatal chronic hypoxia impairs pathways critical to pulmonary vascular development that are coupled to abnormalities in lung structure and function through dysregulation in cell growth and proliferation. To address this hypothesis, we employed an animal model of pregnant sheep exposed to high altitude hypoxia at the White Mountain Research Station, which has an altitude of 3801 meters. Hypoxic pregnant sheep were housed at altitude during gestation for ~110 days out of 138-141 days of pregnancy while normoxic counterparts were kept at 700 meters. Animals were transferred to Loma Linda at 355 meters and fetal lambs studied at ~140 days of gestation. Fetal plasma samples were collected for exosomal miRNA analysis and pulmonary arteries were collected for proteomic and metabolomic analysis. Ingenuity pathway analysis and other bioinformatic tools were used to interrogate regulatory mechanisms and pathways and the web of molecular interactions affected by hypoxia. Antenatal hypoxic stress caused up and down regulation of a limited number of plasma exosomal miRNAs, pulmonary arterial metabolites and proteins, with discrete interconnections between the various analytes and molecules. There were marked changes in upstream regulators and markers that point to increased oxidative stress and inflammatory response along with pronounced downregulation of matrix proteins and phenotypic markers of vascular smooth muscle cell differentiation. Pathway analyses indicate antenatal chronic hypoxia dysregulates growth and proliferation of vascular cells and impinges on cell migration. While these data require additional study and verification, they provide new insights in the understanding of mechanisms underlying the development of pulmonary hypertension in the newborn following antenatal hypoxia. This work was supported by the National Institutes of Health Grants NIH R01HL155295, R01HL149608, R03HD098477, P01HD083132, and U24DK097154. Additional support was provided by the Loma Linda University School of Medicine, A pilot Project through the West Coast Metabolomics Center, the University of Redlands Summer Research Program, and the Walter E. Macpherson Society. 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.

Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury.

Traumatic brain injury (TBI) remains a significant public health concern, with no effective therapeutic interventions to ameliorate the enduring consequences. The prevailing understanding of TBI pathophysiology indicates a central role for vascular dysfunction. Transforming growth factor-β (TGF-β) is a multifunctional cytokine crucial for vascular development. Aberrant TGF-β signaling is implicated in vascular pathologies associated with various neurological conditions. We recently developed a novel small molecule drug, C381, a TGF-β activator with the ability to restore lysosomal function. Here we used a mouse model of repetitive mild TBI (mTBI) to examine whether C381 would attenuate vascular injury. We first employed RNA-seq analysis to investigate the gene expression patterns associated with mTBI and evaluated the therapeutic potential of C381 in mitigating these changes. Our results demonstrate distinct mTBI-related gene expression signatures, prominently implicating pathways related to vascular integrity and endothelial function. Notably, treatment with C381 reversed these mTBI-induced gene expression changes. Immunohistochemical analysis further corroborated these findings, revealing that C381 treatment attenuated vascular damage in mTBI-affected brain tissue. These findings strongly support the potential clinical usefulness of C381 as a novel therapeutic intervention for mTBI.

Vascular Organization: Lessons from Development and Disease.

Organ formation requires tight coordination with vascular growth. Intricate networks of blood vessels course through all organs and tissues and are composed of both endothelial cells (ECs) and associated mural cells. Despite decades of research into the biology of blood vessel formation and homeostasis, little is known about how the vasculature ensures its properly coordinated growth and intimate development with the cells of different organs. Even more mystifying is how a highly dynamic endothelium quiesces to differentiate into mature vessels, and how disruption of this mature quiescence results in pathological conditions. Interestingly, both intra- and interorgan vascular architecture hold critical importance to the maintenance of blood vessels, as the rate of flow and supply of supportive angiogenic factors can be altered with deleterious effects. In this article, we review the basic mechanisms of blood vessel formation and maintenance with an emphasis on organ-specific vascular development, and we examine the case of transient pulmonary arteriovenous malformations as a case study of vascular homeostatic mechanisms.

Ontogeny of the multiple cambial variants and secondary growth in some species of Merremia and related genera (Convolvulaceae)

ABSTRACT The present study investigates the stem anatomy and development of cambial variants in 10 species of Merremia and related genera (Convolvulaceae) were compared histologically. Among them, Camonea kingii, C. umbellata, Distimake aegyptius, D. quinquefolius, D. vitifolius and M. hederacea increased their stem diameter by initiating successive cambia. In contrast, remaining species showed regular secondary growth. These species also demonstrated inversely oriented vascular elements, phloem wedges, intraxylary cambia, parenchyma proliferation and development of radial vascular cylinders in the large rays of xylem. Phloem wedges developed by the differential activity of regular cambium in small segments by depositing only unlignified parenchyma internally whereas nearby sectors of the cambium behaved regularly. After the development of intraxylary protophloem from procambial derivatives, additional phloem was formed from the pith cells and by initiating intraxylary cambium. Initially, intraxylary cambium was unifacial in all species, but eventually became bifacial (except M. emarginata) and deposited both xylem and phloem. In conclusion, Merremia species use all feasible methods to generate new vascular elements to compensate for the supply of water, nutrients and photosynthate. Inter-and intraxylary phloem development appears to provide an additional and safe conduit for long-distance vertical conduction, whereas radial vascular cylinders facilitate radial conduction.

Nattokinase attenuates endothelial inflammation through the activation of SRF and THBS1

Natto contains a potent fibrinolytic enzyme called nattokinase (NK), which has thrombolytic, antihypertensive, antiatherosclerotic and lipid-lowering effects. Although NK has been recognized for its beneficial effect on humans with atherosclerotic cardiovascular disease (ASCVD), the underlying mechanisms involved in vascular inflammation-atherosclerosis development remain largely unknown. The current study aimed to explore the effects of NK on gene regulation, autophagy, necroptosis and inflammasome in vascular inflammation. The transcriptional profiles of NK in endothelial cells (ECs) by RNA sequencing (RNA-seq) revealed that NK affected THBS1, SRF and SREBF1 mRNA expression. In Q-PCR analysis, SRF and THBS1 were upregulated but SREBF1 was unaffected in ECs treated with NK. NK treatment induced autophagy and inhibited NLRP3 inflammasome and necroptosis in ECs. Furthermore, the inhibition of SRF or THBS1 by siRNA suppressed autophagy and enhanced the NLRP3 inflammasome and necroptosis. In a mouse model, NK reduced vascular inflammation by activating autophagy and inhibiting NLRP3 inflammasome and necroptosis. Our findings provide the first evidence that NK upregulates SRF and THBS1 genes, subsequently increasing autophagy and decreasing necroptosis and NLRP3 inflammasome formation to reduce vascular inflammation. Therefore, NK could serve as nutraceuticals or adjuvant therapies to reduce vascular inflammation and possible atherosclerosis progression.