Coronary Blood Vessels Research Articles

Purinergic Signaling in the Cardiovascular System.

There is nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory-motor nerves, as well as in intracardiac neurons. Centers in the brain control heart activities and vagal cardiovascular reflexes involve purines. Adenine nucleotides and nucleosides act on purinoceptors on cardiomyocytes, AV and SA nodes, cardiac fibroblasts, and coronary blood vessels. Vascular tone is controlled by a dual mechanism. ATP, released from perivascular sympathetic nerves, causes vasoconstriction largely via P2X1 receptors. Endothelial cells release ATP in response to changes in blood flow (via shear stress) or hypoxia, to act on P2 receptors on endothelial cells to produce nitric oxide, endothelium-derived hyperpolarizing factor, or prostaglandins to cause vasodilation. ATP is also released from sensory-motor nerves during antidromic reflex activity, to produce relaxation of some blood vessels. Purinergic signaling is involved in the physiology of erythrocytes, platelets, and leukocytes. ATP is released from erythrocytes and platelets, and purinoceptors and ectonucleotidases are expressed by these cells. P1, P2Y1, P2Y12, and P2X1 receptors are expressed on platelets, which mediate platelet aggregation and shape change. Long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides promote migration and proliferation of vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis, vessel remodeling during restenosis after angioplasty and atherosclerosis. The involvement of purinergic signaling in cardiovascular pathophysiology and its therapeutic potential are discussed, including heart failure, infarction, arrhythmias, syncope, cardiomyopathy, angina, heart transplantation and coronary bypass grafts, coronary artery disease, diabetic cardiomyopathy, hypertension, ischemia, thrombosis, diabetes mellitus, and migraine.

Numerical Study of the Effects of Aneurysm and Stenosis in the Left Coronary Artery on the Human Blood Stream

The heart is the most important muscular organ in human's body, which pumps blood through the arteries to supply the body with oxygen and nutrients. The heart is supplied by the coronary blood vessel; therefore, the effect of aneurysm and stenosis in left coronary artery on the velocity of blood, wall shear stress of artery and mass flow rate of blood have been investigated in this study. The simulation program (ANSYS Fluent) was used to execute the numerical study. Typical geometry of left coronary artery and physiological parameters of human blood values were obtained from measured values reported in literature. The problem of the effect of the aneurysm and stenosis on the human blood stream has been solved numerically under three conditions, healthy artery and two infected cases (30%, 50%) percentage of aneurysm in left main stem (LMS) and stenosis in left anterior descending (LAD). It has been shown, in stenosis region that the velocity of blood will suffer fast flowing and an increase in the shear stress on the artery wall, in contrast with the aneurysm case, blood velocity becomes slow and low wall shear stress. Also irregularity was shown in mass flow rate of blood in the left coronary artery which suffers from aneurysm and stenosis compared with healthy artery.

Rheological aspects of coronary artery and coronary small blood vessel diseases (Syndrome X)

Rheological aspects of coronary artery and coronary small blood vessel diseases (Syndrome X)

Automatic coronary artery segmentation based on multi-domains remapping and quantile regression in angiographies

Coronary artery disease has become the most dangerous diseases to human life. And coronary artery segmentation is the basis of computer aided diagnosis and analysis. Existing segmentation methods are difficult to handle the complex vascular texture due to the projective nature in conventional coronary angiography. Due to large amount of data and complex vascular shapes, any manual annotation has become increasingly unrealistic. A fully automatic segmentation method is necessary in clinic practice. In this work, we study a method based on reliable boundaries via multi-domains remapping and robust discrepancy correction via distance balance and quantile regression for automatic coronary artery segmentation of angiography images. The proposed method can not only segment overlapping vascular structures robustly, but also achieve good performance in low contrast regions. The effectiveness of our approach is demonstrated on a variety of coronary blood vessels compared with the existing methods. The overall segmentation performances si, fnvf, fvpf and tpvf were 95.135%, 3.733%, 6.113%, 96.268%, respectively.

Glycogen Synthase Kinase 3β Inhibition Improves Myocardial Angiogenesis and Perfusion in a Swine Model of Metabolic Syndrome.

BackgroundInhibition of glycogen synthase kinase 3β (GSK‐3β) has been reported to be cardioprotective during stressful conditions.Methods and ResultsPigs were fed a high‐fat diet for 4 weeks to develop metabolic syndrome, then underwent placement of an ameroid constrictor to their left circumflex artery to induce chronic myocardial ischemia. Two weeks later, animals received either: no drug (high cholesterol control group [HCC]) or a GSK‐3β inhibitor (GSK‐3β inhibited group [GSK‐3βI]), which were continued for 5 weeks, followed by myocardial tissue harvest. Coronary blood flow and vessel density were significantly increased in the GSK‐3βI group compared to the HCC group. Expression levels of the following proteins were greater in the GSK‐3βI group compared to the HCC group: vascular endothelial growth factor receptor 1 , vascular endothelial cadherin, γ‐catenin, β‐catenin, protein kinase B, phosphorylated forkhead box O1, and superoxide dismutase 2.ConclusionsIn the setting of metabolic syndrome, inhibition of GSK‐3β increases blood flow and vessel density in chronically ischemic myocardium. We identified several angiogenic, cell survival, and differentiation pathways that include β‐catenin signaling and AKT/FOXO1, through which GSK‐3β appears to improve vessel density and blood flow. These results may provide a potential mechanism for medical therapy of patients suffering from coronary artery disease and metabolic syndrome.

Dobutamine Stress Echocardiography in Patients with Dilated Cardiomyopathy

Abstract A clear distinction between two of the most common forms of dilated cardiomyopathy is very important due to their different prediction and therapeutic approaches. Dobutamine stress echocardiography appears to be a noninvasive selection method due to its clear differentiation potential. Major factors influence test interpretation, resulting in a wide interval of diagnostic accuracy for this test. Fraction flow reserve (FFR) is a novel invasive method for estimating coronary artery stenosis responsible for myocardium ischaemia. Decisions about lesion significance in coronary blood vessels have thus far been based on angiographic estimations, but this approach is being replaced by FFR measurements, which serve as a new gold standard and involve a noninvasive test. The goal of this study was to clearly differentiate two forms of dilated cardiomyopathies through analysis of the segmented mobility of the left ventricular wall. Fifty patients were analysed: 20 with ischaemic dilated cardiomyopathy, which was confirmed not only through coronary angiography but also functionally through FFR measurement, and 30 patients with nonischaemic dilated cardiomyopathy, which was confirmed by coronary angiography. A standard dobutamine stress echocardiography protocol was implemented. A positive dobutamine stress echocardiography test was defined as the presence of emerging incidents in segment contractility or worsening of existing incidents in at least one segment. Statistically relevant diff erences in the movement dynamics of a number of differently characterised segments during the observed time intervals (ANOVA p=0.000) was noted in both groups of patients, as was variation in the index value of the summarized mobility of the left chamber wall. In patients with ischaemic cardiomyopathies, regional contractility worsened at the maximum dose of dobutamine; in contrast, this feature slightly improved in nonischaemic cardiomyopathy patients. The results indicate that by analysing segmental motion, these two forms of dilated cardiomyopathies can be differentiated with high sensitivity (Sn=90%) and specificity (Sp=98%), which can be interpreted as concrete evidence of truly ischaemic lesions in coronary blood vessels.

Blood Flow Modelling of Linear and Sequential Bypass Coronal Vessels of the Heart

The paper presents results of blood flow parameters numerical simulation in the coronal vessels of the left coronary artery. Described mathematical model characterizing the hemodynamics of the coronary artery blood vessels allows the simulation of blood flow parameters changes in the coronal vessels subjected to bypass surgery. On the basis of this model blood flow parameters of linear and sequential bypasses types were calculated and compared.

CXCL12 And Vascular Maturation Of The Coronary System During Heart Development

Elucidating the mechanisms involved in the patterning of coronary blood vessels in the embryo will help to improve therapies for coronary perfusion in the injured heart. In the past few years, there have been significant efforts and advances in the understanding of coronary vessel development. The major endothelial cell sources that provide coronary endothelial progenitors to the heart are the sinus venosus (the vein that delivers the venous return) and the endocardium, although the respective contribution from each source is debated. Angiogenic sprouts from the sinus venosus reach the ventricles starting at E11.5 in the mouse and form a vascular plexus in the subepicardial space. This primitive plexus undergoes a complex and incompletely understood process of vascular maturation that involves pruning, branching and reorganization into a hierarchical network of superficial veins and intramyocardial arteries. The main branches of the coronary arteries ultimately connect to the aorta through the coronary ostia by E13.5 – E14.0.CXCL12 (also known as stromal derived factor 1, SDF1) is a chemokine that acts through the G protein‐coupled receptor CXCR4. Global deficiency of Cxcl12 or Cxcr4 as well as endothelial deletion of Cxcr4 result in vascular defects in the mouse kidney and gut, but these defects do not explain the associated late gestation lethality. We hypothesized that coronary vascular defects might underlie the embryonic lethality of CXCL12 deficiency.Cxcl12 and Tie2Cre/Cxcr4 mutants form an initial coronary vascular plexus, which then fails to remodel into a hierarchical network of mature vessels, resulting in the absence of the major intramyocardial coronary arteries, hemorrhage and reduced ventricular wall perfusion. The coronary veins were mostly unaffected, and the basis of the selectivity of CXCL12 on the arterial side of the vasculature is still unclear.In vitro, CXCL12 does not induce sprouting of endothelial cells from beads embedded in a fibrin gel matrix, but instead promotes maturation of vascular sprouts preformed in response to VEGF, by increasing tube elongation, vessel branching, anastomosis and intussusception, all features of mature blood vessel networks. These features were abolished in the presence of AMD3100, a CXCR4 inhibitor. Thus, CXCL12 does not initiate vasculogenesis but rather promotes further remodeling of a plexus that is initially induced by VEGF.We conclude that failed maturation of the coronary system explains the late‐gestation lethality of Cxcl12 mutants, and highlight the role of CXCL12 as an organ‐specific arterial maturation factor of particular relevance in the coronary vasculature. Our current studies are aimed at defining the role of CXCL12 in reprogramming of venous endothelial cells from the sinus venosus into coronary arterial endothelium.Support or Funding InformationThis work was supported by NIH grant HL070123 to H.M.S. and grant 14BGIA20500059 to S.R.K. from the American Heart Association. S.C. was supported by a Postdoctoral Fellowship from the American Heart Association. H.S. was supported by a Postdoctoral Fellowship from the California Institute for Regenerative Medicine.

Primitive Embryonic Macrophages are Required for Coronary Development and Maturation.

It is now recognized that macrophages residing within developing and adult tissues are derived from diverse progenitors including those of embryonic origin. Although the functions of macrophages in adult organisms are well studied, the functions of macrophages during organ development remain largely undefined. Moreover, it is unclear whether distinct macrophage lineages have differing functions. To address these issues, we investigated the functions of macrophage subsets resident within the developing heart, an organ replete with embryonic-derived macrophages. Using a combination of flow cytometry, immunostaining, and genetic lineage tracing, we demonstrate that the developing heart contains a complex array of embryonic macrophage subsets that can be divided into chemokine (C-C motif) receptor 2(-) and chemokine (C-C motif) receptor 2(+) macrophages derived from primitive yolk sac, recombination activating gene 1(+) lymphomyeloid, and Fms-like tyrosine kinase 3(+) fetal monocyte lineages. Functionally, yolk sac-derived chemokine (C-C motif) receptor 2(-) macrophages are instrumental in coronary development where they are required for remodeling of the primitive coronary plexus. Mechanistically, chemokine (C-C motif) receptor 2(-) macrophages are recruited to coronary blood vessels at the onset of coronary perfusion where they mediate coronary plexus remodeling through selective expansion of perfused vasculature. We further demonstrate that insulin like growth factor signaling may mediate the proangiogenic properties of embryonic-derived macrophages. Together, these findings demonstrate that the embryonic heart contains distinct lineages of embryonic macrophages with unique functions and reveal a novel mechanism that governs coronary development.

Pharmacology of the Adenosine A3 Receptor in the Vasculature and Essential Hypertension.

BackgroundEssential hypertension is considered to be a multifactorial disorder and its aetiology has yet to be clearly identified. As the adenosine receptors have a significant role in mediating vasodilation, alterations in their structures or signalling pathways may be involved in the development of hypertension. This study aimed to measure the expression of adenosine A3 receptors in a range of cardiovascular tissues and determine whether they could be altered with essential hypertension, and to functionally test responses to adenosine A3 receptor agonists in coronary blood vessels using the isolated perfused heart preparation.MethodsmRNA samples from cardiovascular tissues and a range of blood vessels were collected from 10 week old male spontaneously hypertensive rats and age-gender matched Wistar rats (n = 8). The Langendorff heart perfusion preparation was used to characterise adenosine A3 receptor mediated coronary vasodilation in the rat heart.ResultsAdenosine A3 receptor agonists induced coronary vasodilation. The expression of adenosine A3 receptors in cardiovascular tissues was altered in a tissue-specific pattern. Specifically, down-regulation of adenosine A3 receptor expression occurred in hypertensive hearts, which might be associated with attenuated vasodilator responses observed in coronary vessels to adenosine A3 receptor agonists.ConclusionsThis study demonstrated alterations in the expression of adenosine A3 receptors occurred in a tissue specific mode, and reduced adenosine A3 receptor mediated coronary vasodilation in hearts from spontaneously hypertensive rats. Our findings with regard to changes in the adenosine A3 receptor in hypertensive hearts suggest that adenosine A3 receptor might play a role in the physiopathology of essential hypertension and potentially open the way to pharmacologic manipulation of vasomotor activity by the use of adenosine A3 receptor agonists.

Congenital coronary artery anomalies: a bridge from embryology to anatomy and pathophysiology—a position statement of the development, anatomy, and pathology ESC Working Group

Congenital coronary artery anomalies are of major significance in clinical cardiology and cardiac surgery due to their association with myocardial ischaemia and sudden death. Such anomalies are detectable by imaging modalities and, according to various definitions, their prevalence ranges from 0.21 to 5.79%. This consensus document from the Development, Anatomy and Pathology Working Group of the European Society of Cardiology aims to provide: (i) a definition of normality that refers to essential anatomical and embryological features of coronary vessels, based on the integrated analysis of studies of normal and abnormal coronary embryogenesis and pathophysiology; (ii) an animal model-based systematic survey of the molecular and cellular mechanisms that regulate coronary blood vessel development; (iii) an organization of the wide spectrum of coronary artery anomalies, according to a comprehensive anatomical and embryological classification scheme; (iv) current knowledge of the pathophysiological mechanisms underlying symptoms and signs of coronary artery anomalies, with diagnostic and therapeutic implications. This document identifies the mosaic-like embryonic development of the coronary vascular system, as coronary cell types differentiate from multiple cell sources through an intricate network of molecular signals and haemodynamic cues, as the necessary framework for understanding the complex spectrum of coronary artery anomalies observed in human patients.

Improved Bat algorithm for the detection of myocardial infarction

The medical practitioners study the electrical activity of the human heart in order to detect heart diseases from the electrocardiogram (ECG) of the heart patients. A myocardial infarction (MI) or heart attack is a heart disease, that occurs when there is a block (blood clot) in the pathway of one or more coronary blood vessels (arteries) that supply blood to the heart muscle. The abnormalities in the heart can be identified by the changes in the ECG signal. The first step in the detection of MI is Preprocessing of ECGs which removes noise by using filters. Feature extraction is the next key process in detecting the changes in the ECG signals. This paper presents a method for extracting key features from each cardiac beat using Improved Bat algorithm. Using this algorithm best features are extracted, then these best (reduced) features are applied to the input of the neural network classifier. It has been observed that the performance of the classifier is improved with the help of the optimized features.

Evolving Cardiovascular Care for Women: A Decade of Progress

10.2217/FCA.15.24 © 2015 Future Medicine Ltd Cardiovascular disease remains the leading cause of mortality for women in the USA despite admirable progress over the past decade and a continued decline in the number of deaths attributable to heart disease [1]. There remains a gender gap in outcomes as ischemic heart disease in women remains underdiagnosed and inadequately treated. It is important to appreciate that this gap exists as women constitute the majority of people both living with and dying from heart disease [2]. Heart disease is different in women compared with men in ways ranging from the basic biology and biomechanics of their coronary blood vessels to psychosocial factors that influence how they experience symptoms and seek medical care. For example, women are more likely to present with atypical symptoms or anginal equivalents, are less likely to have obstructive coronary disease, and are often older at presentation with more comorbidities present compared with men [3].

Combined Atherosclerotic Lesions of Cerebral and Coronary Blood Vessels: Risk Factors

Data is presented specifying the extent of influence of traditional and novel (C-reactive protein (CRP), fibrinogen, intima-media complex (IMC)) risk-factors of atherosclerotic lesions upon cerebral blood vessels in case of isolated variant vs. combined lesions of coronary and cerebral blood vessels. The role of CRP and fibrinogen as atherosclerotic process development markers is discussed. The most significant risk factors of combined and isolated atherosclerotic lesions of coronary and cerebral blood vessels are discussed important for understanding of this pathology ethiology and pathogenesis. Pathogenetic interrelation of cerebral and cardiac pathology is specified manifesting itself by mutual aggravation in case of atherosclerotic process. Pathophysiologic mechanisms of cerebral and coronary blood vessels’ atherosclerotic lesions are common, hence the risk factors are also analogous, however their import is not identical in case of isolated and combined variants and this feature should be taken into account while working out the approach to this ailment treatment and prophylaxis. Atherosclerotic lesions of arteries from various vascular basins alongside with common pathophysiologic mechanisms also possess a score of peculiarities that predetermine different approaches to their treatment and prophylaxis. Separate risk factors determine predominant localization of pathologic process in certain vascular basins thus identification of isolated and combined coronary and cerebral principal blood vessels atherosclerotic lesions’ risk factors is a subject of profound studies. Thus working out new approaches to cerebrovascular ailments risk prognosis on the basis of cardiovascular ailments risk factors as well as existing prophylactic measures monitoring is actual for contemporary medicine.

Impact of adipose specific peptides on the course and prognosis of myocardial heart attacks

Tests have shown that adipose tissue is very important in the production of chemical substances that have a major impact on atherosclerosis. The basic fat cells adiposity is very active in bio secretion hormones and other substances. Adiposities secrete chemical substances such as leptin, resistin, adiponectin, and others who participate in metabolic processes. One of the most important adipocytokine affecting the formation and the regression of atheromas plaque in the coronary blood vessels are adiponectin and resistin. So our aim was to determine the value of the concentration of adiponectin and resistin on patient with myocardial heart attack and determine their correlation with the control group of healthy subjects. In this study were included 68 subjects, 40 with myocardial heart attacks and 28 control groups of normal healthy. In the group with myocardial 78.6% of respondents were male and 21.4% female. Tests have shown that the concentration of adiponectin in the group with myocardial heart attack was significantly lower than the control group (4.94 to 6.74, p=0.043, p<0.05. In the same study group average value of resistin was significantly higher than in the control group (15.73 to 7.88, p=0.001, p<0.01) (Student's t-test, p = 0.581, p> 0.05). All this indicates that in patients with myocardial heart attack there is a decline in the concentration of adiponectin, which has cardio protective effect. The increase in resistin in myocardial heart attack in directly related to the appearance of athermanous plaques in the coronary blood vessels and has a bad prognostic significance.

Evaluation of Long-Term Changes in the Levels of Inflammatory Factors during Postoperative Period in Patients with Acute Coronary Syndrome without STSegment Elevation Undergone Coronary Artery Bypass Surgery

Objective: One of the most effective and widely used methods of myocardial revascularization in patients with acute coronary syndromes is coronary artery bypass surgery (CABG). Chronic inflammation plays a significant role in the destabilization of atherosclerotic plaques in acute forms of ischemic heart disease and also in relapse of myocardial ischemia after myocardial revascularization. Ischemic myocardial injury is associated with activation of molecular and cellular inflammatory factors, the most important of which are cytokines, cell adhesion molecules (CAM) and leukocytes. Changing in the concentration of these agents during postoperative period reflects the intensity of the inflammatory and reparative processes in the myocardium. In this context, it is relevant to evaluate the long-term dynamics of inflammatory markers in the patients undergone coronary artery bypass grafting to predict the possible exacerbation of coronary heart disease. Methods: The study involved 130 patients who underwent CABG surgery with acute coronary syndrome without ST-segment elevation. The comparison group consisted of 28 patients who suffered from stable coronary artery disease (average age 50.9 ± 1.2 years) with a history of MI, no earlier than 6 months prior to study entry. The levels of serum inflammatory markers (ICAM-1, TNF-α, IL-6, leukocytes) were measured before operation and 6.12, 24 and 48 months after CABG. Results: The study showed that soluble intercellular adhesion molecule-1 (ICAM-1) and leukocyte levels in patients with non-ST elevation acute coronary syndrome gradually decreased during follow-up period in comparison with preoperative rates. sICAM-1 level increased up to 48 month and tended to preoperative value. There were no changes in tumor necrosis factor- alpha (TNF-α) and interleukin-6 (IL-6) levels during the whole follow-up period. TNF-α level in the patients with NSTE ACS before surgery have not differed from the level in the patients with stable ischemic heart disease (62.0 ± 9.8 pg/ml and 51.0 ± 6.8 pg/ml; p>0.05). TNF-α serum level has remained unchanged in the patients after CABG. Preoperative levels of IL-6 did not differ significantly among the patients with NSTE ACS and stable coronary artery disease (34.5 ± 3.6 pg/ml and 28.6 ±3.1 pg/ml; p>0.05). The IL-6 levels remained practically unchanged over time. Conclusion: According to the results we can suggest, that further maintenance and development of the inflammatory process after CABG will contribute to the progression of coronary heart disease preserving the risk of exacerbation and reocclusion of coronary blood vessels.

Cardiac purinergic signalling in health and disease.

This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

Recent developments in vascular biology.

The field of vascular biology has transformed dramatically in recent years as new research has elucidated complex roles of novel proteins, stem/progenitor/hematopoietic cells, and miRNAs as well as redox signaling in vascular development, vascular tone regulation and disease in preclinical models and clinical settings. Review of this body of work highlights seminal findings and new developments that emphasize and illuminate underlying principles and historical connections. In the 1980s, there was the frenzied search for the identity of the Endothelium-Derived Relaxing Factor (EDRF; ie, NO).1,2 In the 1990s, the elucidation of myriad EDHFs (hyperpolarizing factors, eg, H2O2, K+, arachidonic acid metabolites) expanded endothelial cell complexity beyond NO.3–5 In the 2000s, the endothelial cell generation and overall cardiovascular effects of H2S were hotly pursued.6,7 In the 2010s, the role of the perivascular adipose tissue (PVAT) derived relaxing and contractile factors in vascular regulation under physiological and disease promoting conditions (eg, diet-induced obesity, metabolic syndrome) has emerged as a new integrative vascular issue of import because of the obesity epidemic.8 Critically important mechanisms continue to be sources of interest and renewed research. Indeed, the panoply of endothelium-derived factors that regulate vascular tone continues to grow, and identifying new ones will only enhance our understanding of the diverse factors that regulate vascular tone and blood flow in context-dependent ways. As elucidated in the article by Zhang et al, entitled “H2O2-induced dilation in human coronary arterioles: role of protein kinase G dimerization and large-conductance Ca2+-activated K+ channel activation,” redox-mediated VSMC K+-channel opening ultimately leads to relaxation and dilation in coronary blood vessels.9 Similarly, PPAR-γ stimulated Regulatory G-protein S 5 (RGS5)-control of Protein Kinase C-mediated opening of calcium-activated …

Tbx5 Is Required for Avian and Mammalian Epicardial Formation and Coronary Vasculogenesis

Holt-Oram syndrome is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and the role of Tbx5 in mammalian coronary vasculogenesis, remains largely unknown. To evaluate the consequences of altered Tbx5 gene dosage during proepicardial organ and epicardial development in the embryonic chick and mouse. Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick proepicardial organ and proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/)) impaired normal proepicardial organ cell development, inhibited epicardial and coronary blood vessel formation, and altered developmental gene expression. The generation of epicardial-derived cells and their migration into the myocardium were impaired between embryonic day (E) 13.5 to 15.5 in mutant hearts because of delayed epicardial attachment to the myocardium and subepicardial accumulation of epicardial-derived cells. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wild-type hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by hypoxia inducible factor-1α upregulation and increased binding of hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity when compared with wild-type mice. Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and in mouse coronary vascular formation.

De novo formation of a distinct coronary vascular population in neonatal heart

The postnatal coronary vessels have been viewed as developing through expansion of vessels formed during the fetal period. Using genetic lineage tracing, we found that a substantial portion of postnatal coronary vessels arise de novo in the neonatal mouse heart, rather than expanding from preexisting embryonic vasculature. Our data show that lineage conversion of neonatal endocardial cells during trabecular compaction generates a distinct compartment of the coronary circulation located within the inner half of the ventricular wall. This lineage conversion occurs within a brief period after birth and provides an efficient means of rapidly augmenting the coronary vasculature. This mechanism of postnatal coronary vascular growth provides avenues for understanding and stimulating cardiovascular regeneration following injury and disease.