Cardiovascular Regeneration Research Articles

Mesenchymal stem cells as future treatment for cardiovascular regeneration and its challenges.

Cardiovascular diseases (CVDs), particularly stroke and myocardial infarction (MI) contributed to the leading cause of death annually among the chronic diseases globally. Despite the advancement of technology, the current available treatments mainly served as palliative care but not treating the diseases. However, the discovery of mesenchymal stem cells (MSCs) had gained a consideration to serve as promising strategy in treating CVDs. Recent evidence also showed that MSCs are the strong candidate to be used as stem cell therapy involving cardiovascular regeneration due to its cardiomyogenesis, anti-inflammatory and immunomodulatory properties, antifibrotic effects and neovascularization capacity. Besides, MSCs could be used for cellular cardiomyoplasty with its transdifferentiation of MSCs into cardiomyocytes, paracrine effects, microvesicles and exosomes as well as mitochondrial transfer. The safety and efficacy of utilizing MSCs have been described in well-established preclinical and clinical studies in which the accomplishment of MSCs transplantation resulted in further improvement of the cardiac function. Tissue engineering could enhance the desired properties and therapeutic effects of MSCs in cardiovascular regeneration by genome-editing, facilitating the cell delivery and retention, biomaterials-based scaffold, and three-dimensional (3D)-bioprinting. However, there are still obstacles in the use of MSCs due to the complexity and versatility of MSCs, low retention rate, route of administration and the ethical and safety issues of the use of MSCs. The aim of this review is to highlight the details of therapeutic properties of MSCs in treating CVDs, strategies to facilitate the therapeutic effects of MSCs through tissue engineering and the challenges faced using MSCs. A comprehensive review has been done through PubMed and National Center for Biotechnology Information (NCBI) from the year of 2010 to 2021 based on some specific key terms such as 'mesenchymal stem cells in cardiovascular disease', 'mesenchymal stem cells in cardiac regeneration', 'mesenchymal stem cells facilitate cardiac repairs', 'tissue engineering of MSCs' to include relevant literature in this review.

Emerging Strategies in Mesenchymal Stem Cell-Based Cardiovascular Therapeutics.

Cardiovascular diseases continue to challenge global health, demanding innovative therapeutic solutions. This review delves into the transformative role of mesenchymal stem cells (MSCs) in advancing cardiovascular therapeutics. Beginning with a historical perspective, we trace the development of stem cell research related to cardiovascular diseases, highlighting foundational therapeutic approaches and the evolution of cell-based treatments. Recognizing the inherent challenges of MSC-based cardiovascular therapeutics, which range from understanding the pro-reparative activity of MSCs to tailoring patient-specific treatments, we emphasize the need to refine the pro-regenerative capacity of these cells. Crucially, our focus then shifts to the strategies of the fourth generation of cell-based therapies: leveraging the secretomic prowess of MSCs, particularly the role of extracellular vesicles; integrating biocompatible scaffolds and artificial sheets to amplify MSCs' potential; adopting three-dimensional ex vivo propagation tailored to specific tissue niches; harnessing the promise of genetic modifications for targeted tissue repair; and institutionalizing good manufacturing practice protocols to ensure therapeutic safety and efficacy. We conclude with reflections on these advancements, envisaging a future landscape redefined by MSCs in cardiovascular regeneration. This review offers both a consolidation of our current understanding and a view toward imminent therapeutic horizons.

Dihydrotestosterone Augments the Angiogenic and Migratory Potential of Human Endothelial Progenitor Cells by an Androgen Receptor-Dependent Mechanism.

Endothelial progenitor cells (EPCs) play a critical role in cardiovascular regeneration. Enhancement of their native properties would be highly beneficial to ensuring the proper functioning of the cardiovascular system. As androgens have a positive effect on the cardiovascular system, we hypothesized that dihydrotestosterone (DHT) could also influence EPC-mediated repair processes. To evaluate this hypothesis, we investigated the effects of DHT on cultured human EPCs' proliferation, viability, morphology, migration, angiogenesis, gene and protein expression, and ability to integrate into cardiac tissue. The results showed that DHT at different concentrations had no cytotoxic effect on EPCs, significantly enhanced the cell proliferation and viability and induces fast, androgen-receptor-dependent formation of capillary-like structures. DHT treatment of EPCs regulated gene expression of androgen receptors and the genes and proteins involved in cell migration and angiogenesis. Importantly, DHT stimulation promoted EPC migration and the cells' ability to adhere and integrate into murine cardiac slices, suggesting it has a role in promoting tissue regeneration. Mass spectrometry analysis further highlighted the impact of DHT on EPCs' functioning. In conclusion, DHT increases the proliferation, migration, and androgen-receptor-dependent angiogenesis of EPCs; enhances the cells' secretion of key factors involved in angiogenesis; and significantly potentiates cellular integration into heart tissue. The data offer support for potential therapeutic applications of DHT in cardiovascular regeneration and repair processes.

Tissue Engineering for Cardiovascular Regeneration: Brief Review on Scaffold Fabrication

Tissue engineering is the combination of engineering and fundamental sciences to develop an artificial organ that derived from the tissue human sources. It involves the construction of three main pillars include cell sources, scaffold materials and biological factors. These three important elements are necessary to be incorporated and integrated well, to construct a functional artificial tissue engineering product. Few applications can be associated with the expansion of tissue engineering where cardiovascular regeneration is one of the targets of tissue engineering. Among the fabrication techniques, electrospinning, three-dimensional printing, molding and decellularization, are four engineering methods that are commonly used in fabricating scaffolds for cardiovascular tissue engineering. One of the purposes of the emerging of cardiovascular tissue engineering is the limitation of current commercialized patches or membranes that often cause post-complications following the cardiovascular treatments. This review paper covering a brief introduction on the tissue engineering for cardiovascular regeneration, focusing on the scaffold fabrication.

Lin28a cardiomyocyte-specific modified mRNA translation system induces cardiomyocyte cell division and cardiac repair

The mammalian heart has a limited regenerative capacity. Previous work suggested the heart can regenerate during development and immediately after birth by inducing cardiomyocyte (CM) proliferation; however, this capacity is lost seven days after birth. modRNA gene delivery, the same technology used successfully in the two mRNA vaccines against SARS-CoV-2, can prompt cardiac regeneration, cardiovascular regeneration and cardiac protection. We recently established a novel CM-specific modRNA translational system (SMRTs) that allows modRNA translation only in CMs. We demonstrated that this system delivers potent intracellular genes (e.g., cell cyclepromoting Pkm2), which are beneficial when expressed in one cell type (i.e., CMs) but not others (non-CMs). Here, we identify Lin28a as an important regulator of the CM cell cycle. We show that Lin28a is expressed in CMs during development and immediately after birth, but not during adulthood. We describe that specific delivery of Lin28a into CM, using CM SMRTs, enables CM cell division and proliferation. Further, we determine that this proliferation leads to cardiac repair and better outcome post MI. Moreover, we identify the molecular pathway of Lin28a in CMs. We also demonstrate that Lin28a suppress Let-7 which is vital for CM proliferation, partially due to its suppressive role on cMYC, HMGA2 and K-RAS.

De novo Biological Coronary Artery Bypass in a Rat Model: Case Report and the Concept of Hybrid Cardiovascular Regeneration

Background: Peripheral blood mononuclear cell-derived progenitor cells (regeneration associated cells: RACs) have been reported to migrate to tissues with inflammation to expedite anti-inflammatory and pro-regeneration actions, but cell sources, administration, timing, dosage, and combined procedures after myocardial ischemia and/or infarction (MI) still remain to be elucidated in preclinical studies. Materials and Methods: Rats with induced MI were treated with intravenous infusion of 5-day culture-primed autologous RACs or control cell transfusion, followed by weekly echocardiography until 4 weeks after MI, at which time pressure-volume relationship (PVR) analyses and histological studies were performed. Results: While most rats treated with autologous RACs infusion after MI developed vascular regeneration from surrounding pericardial tissues and significant functional improvements, one rat developed a de novo coronary artery bypass (φ< 0.3 mm) mimicking surgical bypass grafting (CABG), echocardiography revealed recovered left ventricular (LV) motion, and PVR analyses showed restored LV function as well as histological changes suggesting revascularization and myocardial regeneration. Conclusion: Development of isolated bypass-like structure by RAC therapy after MI led us to consider further surgical as well as biological modifications to expedite biological coronary revascularization and myocardial regeneration. A combination with vascular approaches to provide arterial inflow may increase the rate of complete revascularization and regeneration of cardiomyocytes as hybrid procedure, as they complement each other, to realize cardiovascular regeneration.

Potential Application of Modified mRNA in Cardiac Regeneration.

Heart failure remains the leading cause of human death worldwide. After a heart attack, the formation of scar tissue due to the massive death of cardiomyocytes leads to heart failure and sudden death in most cases. In addition, the regenerative ability of the adult heart is limited after injury, partly due to cell-cycle arrest in cardiomyocytes. In the current post-COVID-19 era, urgently authorized modified mRNA (modRNA) vaccines have been widely used to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, modRNA-based protein replacement may act as an alternative strategy for improving heart disease. It is a safe, effective, transient, low-immunogenic, and integration-free strategy for in vivo protein expression, in addition to recombinant protein and stem-cell regenerative therapies. In this review, we provide a summary of various cardiac factors that have been utilized with the modRNA method to enhance cardiovascular regeneration, cardiomyocyte proliferation, fibrosis inhibition, and apoptosis inhibition. We further discuss other cardiac factors, modRNA delivery methods, and injection methods using the modRNA approach to explore their application potential in heart disease. Factors for promoting cardiomyocyte proliferation such as a cocktail of three genes comprising FoxM1, Id1, and Jnk3-shRNA (FIJs), gp130, and melatonin have potential to be applied in the modRNA approach. We also discuss the current challenges with respect to modRNA-based cardiac regenerative medicine that need to be overcome to apply this approach to heart disease. This review provides a short description for investigators interested in the development of alternative cardiac regenerative medicines using the modRNA platform.

Targeting the redox system for cardiovascular regeneration in aging.

Cardiovascular aging presents a formidable challenge, as the aging process can lead to reduced cardiac function and heightened susceptibility to cardiovascular diseases. Consequently, there is an escalating, unmet medical need for innovative and effective cardiovascular regeneration strategies aimed at restoring and rejuvenating aging cardiovascular tissues. Altered redox homeostasis and the accumulation of oxidative damage play a pivotal role in detrimental changes to stem cell function and cellular senescence, hampering regenerative capacity in aged cardiovascular system. A mounting body of evidence underscores the significance of targeting redox machinery to restore stem cell self-renewal and enhance their differentiation potential into youthful cardiovascular lineages. Hence, the redox machinery holds promise as a target for optimizing cardiovascular regenerative therapies. In this context, we delve into the current understanding of redox homeostasis in regulating stem cell function and reprogramming processes that impact the regenerative potential of the cardiovascular system. Furthermore, we offer insights into the recent translational and clinical implications of redox-targeting compounds aimed at enhancing current regenerative therapies for aging cardiovascular tissues.

Bone marrow vasculature advanced in vitro models for cancer and cardiovascular research.

Cardiometabolic diseases and cancer are among the most common diseases worldwide and are a serious concern to the healthcare system. These conditions, apparently distant, share common molecular and cellular determinants, that can represent targets for preventive and therapeutic approaches. The bone marrow plays an important role in this context as it is the main source of cells involved in cardiovascular regeneration, and one of the main sites of liquid and solid tumor metastasis, both characterized by the cellular trafficking across the bone marrow vasculature. The bone marrow vasculature has been widely studied in animal models, however, it is clear the need for human-specific in vitro models, that resemble the bone vasculature lined by endothelial cells to study the molecular mechanisms governing cell trafficking. In this review, we summarized the current knowledge on in vitro models of bone marrow vasculature developed for cardiovascular and cancer research.

Abstract P129: Cardiovascular Safety Of Severe And Sustained Hypoxia Exposure In Physically Fit Patients Following Myocardial Infarction

In mice, hypoxia exposure corresponding to 8000 m altitude over several weeks induced myocardial proliferation and improved left ventricular ejection fraction following myocardial infarction. To enable translation of these findings from mice to patients with myocardial infarction, we determined whether exposure to severe sustained hypoxia is limited by right ventricular failure secondary to hypoxia-induced pulmonary hypertension. We enrolled three men who suffered myocardial infarctions 49-126 months prior to the study (left ventricular ejection fraction 47±7 %) but were otherwise healthy and one male, healthy control person. We induced hypoxia by adding nitrogen to ambient air until alveolar oxygen partial pressure decreased to 35 mmHg. Normobaric hypoxia was then maintained for 14 consecutive days (FiO2=0.095) corresponding to 6062- 6224 m altitude. We added 1% oxygen over night to ameliorate sleep and prevent acute mountain sickness. We conducted echocardiography at baseline, during hypoxia in hypoxic conditions and 3 days after reconditioning. Measurements included right ventricular to atrial pressure gradient as surrogate for pulmonary artery systolic pressure (PAPsys), tricuspid annulus systolic excursion (TAPSE) and right ventricular (RV) free wall strain. Hypoxia induced pulmonary hypertension, that rapidly abated in recovery (baseline: 35±3 mmHg, hypoxia: 47±9, recovery: 28±1, p=0.0292). TAPSE was not reduced by hypoxic exposure (baseline: 28±3 mmHg, hypoxia: 26±1 recovery: 29±2, p=0.0693) and right ventricular free wall strain was maintained (baseline: -22.4±3.9 mmHg, hypoxia: -24±5.4 recovery: -22.7±1.5, p=0.8493). The healthy control person showed similar responses. No signs or symptoms of right heart failure occurred throughout the study. In highly selected patients with myocardial infarction, substantial normobaric hypoxia induced pulmonary hypertension, however, right ventricular function was well preserved. These observations pave the way for translational studies on hypoxia-induced cardiovascular regeneration and may have implications for patients traveling to high altitude.

A Multimodal Omics Framework to Empower Target Discovery for Cardiovascular Regeneration.

Ischaemic heart disease is a global healthcare challenge with high morbidity and mortality. Early revascularisation in acute myocardial infarction has improved survival; however, limited regenerative capacity and microvascular dysfunction often lead to impaired function and the development of heart failure. New mechanistic insights are required to identify robust targets for the development of novel strategies to promote regeneration. Single-cell RNA sequencing (scRNA-seq) has enabled profiling and analysis of the transcriptomes of individual cells at high resolution. Applications of scRNA-seq have generated single-cell atlases for multiple species, revealed distinct cellular compositions for different regions of the heart, and defined multiple mechanisms involved in myocardial injury-induced regeneration. In this review, we summarise findings from studies of healthy and injured hearts in multiple species and spanning different developmental stages. Based on this transformative technology, we propose a multi-species, multi-omics, meta-analysis framework to drive the discovery of new targets to promote cardiovascular regeneration.

Mechanisms regulating vascular and lymphatic regeneration in the heart after myocardial infarction.

Myocardial infarction, caused by a thrombus or coronary vascular occlusion, leads to irreversible ischaemic injury. Advances in early reperfusion strategies have significantly reduced short-term mortality after myocardial infarction. However, survivors have an increased risk of developing heart failure, which confers a high risk of death at 1 year. The capacity of the injured neonatal mammalian heart to regenerate has stimulated extensive research into whether recapitulation of developmental regeneration programmes may be beneficial in adult cardiovascular disease. Restoration of functional blood and lymphatic vascular networks in the infarct and border regions via neovascularisation and lymphangiogenesis, respectively, is a key requirement to facilitate myocardial regeneration. An improved understanding of the endogenous mechanisms regulating coronary vascular and lymphatic expansion and function in development and in adult patients after myocardial infarction may inform future therapeutic strategies and improve translation from pre-clinical studies. In this review, we explore the underpinning research and key findings in the field of cardiovascular regeneration, with a focus on neovascularisation and lymphangiogenesis, and discuss the outcomes of therapeutic strategies employed to date. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Neonatal Cardiovascular-Progenitor-Cell-Derived Extracellular Vesicles Activate YAP1 in Adult Cardiac Progenitor Cells.

New stem cell and extracellular-vesicle-based therapies have the potential to improve outcomes for the increasing number of patients with heart failure. Since neonates have a significantly enhanced regenerative ability, we hypothesized that extracellular vesicles isolated from Islet-1+ expressing neonatal human cardiovascular progenitors (CPCs) will induce transcriptomic changes associated with improved regenerative capability when co-cultured with CPCs derived from adult humans. In order to test this hypothesis, we isolated extracellular vesicles from human neonatal Islet-1+ CPCs, analyzed the extracellular vesicle content using RNAseq, and treated adult CPCs with extracellular vesicles derived from neonatal CPCs to assess their functional effect. AKT, ERBB, and YAP1 transcripts were elevated in adult CPCs treated with neonatal CPC-derived extracellular vesicles. YAP1 is lost after the neonatal period but can stimulate cardiac regeneration. Our results demonstrate that YAP1 and additional transcripts associated with improved cardiovascular regeneration, as well as the activation of the cell cycle, can be achieved by the treatment of adult CPCs with neonatal CPC-derived extracellular vesicles. Progenitor cells derived from neonates secrete extracellular vesicles with the potential to stimulate and potentially improve functional effects in adult CPCs used for cardiovascular repair.

Abstract 14625: Strategies for Maturation of Cardiovascular Organoids for Modeling Acquired and Inherited Adult-Onset Cardiomyopathies

The development of Induced Pluripotent Stem cells (iPSC) technology has provided a lot of opportunities for disease modeling and cardiovascular regeneration. Two leading limitations of most iPSC-based modeling systems are: the relatively immature phenotype of the generated cardiomyocytes (CMs) (which exhibit fetal-like characteristics and fail to fully emulate the physiology processes of adult myocardium); and the lack of multicellularity (supporting cells such as endothelial cells, cardiac fibroblasts, and smooth muscle cells) facilitating the function of the organoid as an authentic cardiac tissue.The current project aims at engineering mature cardiovascular organoids for modeling acquired and inherited cardiomyopathies left ventricular hypertrophy and inherited hypertrophic cardiomyopathy. The expression of cardiac Troponin I (TnI) isoform 3 is the hallmark of sarcomere maturation.The study planned will be conducted using an iPSC tissue culture system. Cell and tissue maturation was evaluated at the morphological level by confocal microscopy, at the molecular level by RT-qPCR and western blot analysis, and at the functional level by force generation and calcium imaging. Engineered cardiovascular organoids are evaluated by a tailor-made high-throughput robotic system allowing to measure electrophysiological signals. Initial Results: CMs maturation inducing strategies have been implicated by combining metabolic maturation together with factors associated with robust maturation (mTOR inhibitor, hormonal supplements, and steroids). The strategy used resulted in significant maturation as evaluated by molecular markers (significant induction of TNNI3 levels) and physiological ones (shorter contraction duration, relaxation time, and time-to-peak). In addition, protocols for simultaneous maturation of CMs together with endothelial cells, cardiac fibroblasts, and smooth muscle cells have been developed.The project suggested providing a unique opportunity to establish cardiovascular organoid-based platforms for modeling acquired and inherited adult-onset cardiomyopathies. The platform may be used for gaining mechanistic insights, toxicity screening, and target identification as well as drug discovery.

Abstract 14077: Human Placental CDX2 Cells Are Multipotent and Differentiate Robustly to Cardiomyocytes

Regenerative biology hinges on exploration of evolutionarily preserved healing mechanisms to maintain and restore homeostasis. CDX2 is one such conserved factor that regulates trophoblast stem cell differentiation in the placenta. We previously demonstrated that murine placental Cdx2 lineage cells are multipotent and restored cardiac function even in male mice after myocardial infarction. We have now isolated CDX2 cells from over 35 patients’ placentas and studied their properties. Using huCDX2 promoter-driven mCherry lentivirus, CDX2 cells were isolated and multi-omics analyses were carried out versus H9ES cells. In vitro cardiac and vascular differentiation was examined. CDX2 cells expressed HLAG (50.5%±5) and cytokeratin7 (95%±5) supporting a trophoblast progenitor identity. Bulk RNA-seq showed 1065 upregulated genes. Differentially expressed genes like NKX2.5, GATA4 , and TBX5 attribute a cardiac committed progenitor feature to CDX2 cells. CDX2 cells downregulated pluripotency markers negating concerns of any undesirable proliferation. Whole-cell proteome of CDX2 cells revealed 252 unique proteins of which 73 were upregulated involving development and immune modulation including FGF, EFGR, and the Map kinase/ERK pathway crucial for cardiac development, in addition to unique cell surface proteins, which can be utilized in place of lentivirus for live-cell selection. When plated on neonatal murine cardiomyocyte feeders, CDX2 cells robustly differentiated into beating cardiomyocytes expressing cTnT and alpha-actinin. Using an alternate feeder-free method, we observed 80-90% cTnT expression in differentiated CDX2 cardiomyocytes. Additionally, CDX2 cells gave rise to endothelial lineage cells expressing vWF. CDX2 cells further formed tube-like structures on matrigel-based endothelial assays and demonstrated uptake of acetylated LDL suggesting functional endothelial generation. We further demonstrated that CDX2 cells can be passaged and significantly expanded ex vivo (50,000 to 1million cells), while retaining cardiovascular potential. These results bring us closer to translation as placenta-derived CDX2 cells may form the basis for a novel clinical approach to cardiovascular regeneration.

Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart.

Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration. We carried out a comprehensive meta-analysis of integrated single cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularisation. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1 and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularisation. We present a high-resolution single cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development. Myocardial infarction is the leading cause of heart failure, a condition with high morbidity and mortality. Vascular regeneration is vital to tissue survival and functional restoration while a comprehensive understanding of the underpinning mechanisms is lacking. We show that the meta-analysis of single cell RNA-sequencing data excels at deciphering multi-faceted vascular responses conserved between mouse and human following ischaemic injury. We envision that these data will inform future strategies and accelerate therapeutic development for promoting vascular regeneration in the ischaemic heart.

Abstract P1141: Heparinized Alginate And Collagen-based Hydrogels Enhance Localized Vascularization In Ischemic Tissue

Over 800,000 myocardial infarctions (MI) occur annually in the United States alone, 25% of which represent a repeat occurrence further indicating chronic ischemia in the myocardium. Cardiovascular regeneration is largely dependent on the stimulation of blood vessel development for recovering tissue perfusion and modulating ventricular remodeling. The delivery of angiogenic growth factors and cytokines has demonstrated the ability to initiate angiogenesis and vascular network formation in cardiac tissue, with localization of bioactive molecules more effective than systemic delivery. Alginate, with its high biocompatibility and biodegradation, represents a promising hydrogel material for factor delivery due to its high protein loading capacity. We hypothesize that covalently binding heparin to alginate will increase binding and retention to subsequently lengthen the local release duration of vascular-promoting factors. For greater tuning and biointegration, collagen and alginate hydrogel designs were optimized for both injection and co-implantation of a solid film with hiPSC-CM based ECTs in a rat model of myocardial infarction. Injectable and solid formulations showed stiffnesses of 50 +/- 2 kPa and 900 +/- 193 kPa, respectively, which was maintained for up to 6 hours of dry time. Release profiles showed sustained growth factor release, with 65% of the total content released at 7 days and 100% release in 14 days. In vitro evaluation using human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) showed cell viability and primitive network formation. In vivo subcutaneous injections showed host-vessel penetration into the delivered biomaterial within 4 days. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) loaded injections demonstrated an average lumen density of 80 +/- 15 vessels/mm 2 when compared to 4 +/- 1 vessels/mm 2 in the unloaded controls. In conclusion, we have designed a biomaterial system for disparate delivery models and shown successful vascularization of the biomaterial, demonstrating the versatile vascular regenerative capabilities of the hydrogel design.

Abstract P3089: Etv2 Functions As A Pioneer Transcription Factor To Regulate Endothelial Lineage Development And Reprogramming

The vasculature is an essential organ for the delivery of blood and oxygen to all tissues of the body and thus relevant to the treatment of ischemic heart disease. The ETS-related transcription factor 2 (ETV2) is a transcription factor that is both necessary and sufficient for the development of endothelial and blood lineages. However, the molecular mechanism by which ETV2 promotes endothelial and blood development is not known and warrants further investigation. Here, we report that ETV2 functions as a novel pioneer transcription factor that relaxes closed chromatin and regulates endothelial development. Pioneer factors are a subset of transcription factors that bind closed chromatin and promote chromatin relaxation in order to drive the development and reprogramming of cell lineages. By comparing embryonic stem cell differentiation and fibroblast reprogramming models with single cell RNA-seq, ATAC-seq, ChIP-seq and in-vitro nucleosomal binding techniques, we demonstrated that ETV2 was able to bind nucleosomal DNA and function as a pioneer factor independent of the cellular context. We also determined that ETV2 executed a pioneering role by recruiting and directly interacting with the ATP-dependent chromatin remodeling enzyme BRG1 to remodel chromatin around endothelial genes to help maintain an open configuration, resulting in increased H3K27ac deposition. Collectively, these results that define a novel pioneer factor and epigenetic regulatory pathways that govern the specification and differentiation of endothelial progenitor cells, will serve as a platform for targeted therapies to promote cardiovascular regeneration.

Effects of Interval Training Intensity and Curcumin on expression of Endothelial Progenitor Cells mRNA and C Reactive Protein in Elderly Rats Heart.

Endothelial progenitor cells (EPCs) play a role in preventing endothelial dysfunction and increasing the angiogenesis process. Regular training increases these cells. Turmeric Curcumin has anti-inflammatory and anti-atherosclerotic properties. 49 Wistar rats were randomly assigned to control (C), Saline (S), curcumin (cur), moderate interval training (MIT), high interval training (HIT), MIT+curAndHIT+cur. The training groups trained 8 weeks,3 sessions per week and 40 minutes each session at 28 and 34 m / min. 48 hours after the last training, The gene expression of the CD34 and KDR was measured by Real-time PCR and CRP usesthe ELISA method. CD34 and KDR mRNA in cur, MIT and HIT groups showed a significant increase compared to C and Sgroups.The highest levels of CD34 and KDR mRNA were observed in HIT+curgroup. While the increase of CD3 mRNA in HIT group was greater than the cur and MIT groups(P = 0.0001). KDR showed a significant increase in MIT and HIT groups compared to C, S, cur and MIT+cur groups. Serum CRP means significantly decreased in all experimental groups compared to C and S groups. The rate of increase in EPCs mRNA in response to aerobic training is dependent on training intensity. HIT training is likely to be more effective in the repair and development of coronary arteries. These findings can be useful for cell therapy and improve cardiovascular regeneration after injury and myocardial disor-der, especially in elderly conditions.

Effects of dezocine combined with dexmedetomidine on adverse reactions and inflammatory factors in patients undergoing HIPEC after intestinal surgery and its protective effect on the heart in the perioperative period.

The aim of this study was to explore the effects of dezocine combined with dexmedetomidine on adverse reactions and inflammatory factors in patients undergoing hyperthermic intraperitoneal chemotherapy (HIPEC) after intestinal surgery and its protective effect on the heart in the perioperative period. A total of 80 patients treated with HIPEC after intestinal surgery in our hospital from September 2018 to December 2019 were enrolled as research subjects. All patients were evenly divided into two groups using a random number table. As to analgesia and sedation during treatment, dezocine was injected intramuscularly at 30 min before treatment in the control group. Meanwhile, dezocine combined with dexmedetomidine was given in the same way in the observation group. Adverse reactions and changes in numeric rating scale (NRS) pain score during intervention were compared between the two groups. The changes in the levels of inflammatory and myocardial injury-related factors, and vascular endothelial function and regeneration ability among cardiovascular indicators at 12 h after intervention were compared as well. Additionally, the correlations of left ventricular mass index (LVMI) with the changes in the levels of inflammatory factor high-sensitivity C-reactive protein (hs-CRP), myocardial injury-related factor lactic dehydrogenase (LDH), vascular endothelial function indicator endothelin-1 (ET-1) and cardiovascular regeneration ability index vascular endothelial growth factor (VEGF) were analyzed. Compared with control group, the total prevalence rate of severe pain, respiratory depression, nausea and vomiting, diarrhea, and muscle rigidity during intervention was significantly reduced in the observation group (p<0.05). NRS pain score at 1, 4, 8 and 12 h after intervention decreased remarkably in the observation group compared with the control group (p<0.05). Meanwhile, the levels of inflammatory factors tumor necrosis factor-α (TNF-α) and hs-CRP, and myocardial injury-related factors LDH and creatine kinase MB (CKMB) as well as ET-1 at 12 h after intervention declined remarkably in observation group compared with control group (p<0.05). However, the levels of nitric oxide (NO), VEGF and basic fibroblast growth factor (bFGF) rose significantly in the observation group (p<0.05). Besides, LVMI was positively correlated with hs-CRP and LDH, whereas was negatively associated with ET-1 and VEGF (p<0.05). In HIPEC, dezocine combined with dexmedetomidine used for sedation and analgesia is able to effectively reduce adverse reactions and relieve inflammatory responses in vivo, exerting a cardio-protective effect.