The initiation of blood flow and flow induced events in early vascular development

Within a day of gastrulation, the embryonic heart begins to beat and creates blood flow in the developing cardiovascular system. The onset of blood flow completely changes the environment in which the cardiovascular system is forming. Flow provides physiological feedback such that the developing network adapts to cue provided by the flow. Targeted inactivation of genes that alter early blood fluid dynamics induce secondary defects in the heart and vasculature and therefore proper blood flow is known to be essential for vascular development. Though hemodynamics, or blood fluid dynamics, are known to activate signaling pathways in the mature cardiovascular system in pathologies ranging from artherosclerosis to angiogenesis, the role in development has not been as intensively studied. The question arises how blood vessels in the embryos, which initially lack cells types such as smooth muscle cells, differ in their response to mechanical signals from blood flow as compared to the more mature cardiovascular system. Many genes known to be regulated by hemodynamics in the adult are important for developmental angiogenesis. Therefore the onset of blood flow is of primary importance to vascular development. This review will focus on how blood flow initiates and the effects of the mechanical signals created by blood flow on cardiovascular development.     

microRNA:心血管发育及疾病中的重要调控因子

心脏是哺乳动物在胚胎发育时期最早形成的器官,心血管系统的正常发育及功能维持受到精确的调控。近年来,心血管疾病已成为危害人类生命的首要杀手之一,因此,对心血管的发育及疾病发生的机制研究一直是生命科学研究的热点问题。microRNA(miRNA)是一类长约18～25nt的单链非编码小RNA,主要通过结合于靶基因的3'非翻译区抑制靶基因的翻译或导致mRNA降解,从而抑制靶基因的表达。miRNA在许多生物学过程中发挥重要的调控作用,如细胞增殖、分化、凋亡、癌症发生等。最近研究表明,miRNA也参与调控心血管系统的发育和疾病发生过程。在此,该文对miRNA在心血管系统发育和疾病中的作用做一综述。     

Comparative cardiovascular development: improving the conceptual framework

Immature vertebrates-either as an embryo in an egg, as free-living larva, or as an in utero fetus, are clearly not just small versions of adults. Their cardiovascular physiology (and doubtlessly other aspects of physiology) differs from that of adults both qualitatively and quantitatively. Yet, comparative cardiovascular physiologists have been relatively conservative in constructing a new (or at least modified) conceptual framework for the understanding of developmental cardiovascular physiology. We recommend that this framework rely less on the established cardiovascular truisms for adult cardiovascular physiology that are proving to be less useful and in instances even inaccurate for interpreting development of the heart and vasculature. We have suggested that three methodologies in particular be incorporated to a greater extent in studies of comparative cardiovascular development: (a) emphasis on multivariate approaches; (b) differentiation between absolute (extrinsic) and relative (intrinsic) time for development, and; (c) employment of time lines for both intra- and interspecific comparisons of the ontogeny of cardiovascular processes. While certainly none of these approaches are novel and others have previously dwelt at length on their importance in other contexts, we feel that the emerging framework for investigating cardiovascular physiological development would benefit from incorporating these and other approaches into experimental design as well as data analysis. Failing to do so results in a heavy dependence on analytical approaches typically used for adults, and thus under-appreciates the novelty and complexity of the developing vertebrate cardiovascular system.     

Notch signaling in the developing cardiovascular system

The Notch proteins encompass a family of transmembrane receptors that have been highly conserved through evolution as mediators of cell fate. Recent findings have demonstrated a critical role of Notch in the developing cardiovascular system. Notch signaling has been implicated in the endothelial-to-mesenchymal transition during development of the heart valves, in arterial-venous differentiation, and in remodeling of the primitive vascular plexus. Mutations of Notch pathway components in humans are associated with congenital defects of the cardiovascular system such as Alagille syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and bicuspid aortic valves. This article focuses on the role of the Notch pathway in the developing cardiovascular system and congenital human cardiovascular diseases. cardiac development; endothelial-mesenchymal transformation; vasculogenesis; angiogenesis     

Transforming growth factor beta in cardiovascular development and function

Transforming growth factor betas (TGFbetas) are pleiotropic cytokines involved in many biological processes. Genetic engineering and tissue explanation studies have revealed specific non-overlapping roles for TGFbeta ligands and their signaling molecules in development and in normal function of the cardiovascular system in the adult. In the embryo, TGFbetas appear to be involved in epithelial-mesenchymal transformations (EMT) during endocardial cushion formation, and in epicardial epithelial-mesenchymal transformations essential for coronary vasculature, ventricular myocardial development and compaction. In the adult, TGFbetas are involved in cardiac hypertrophy, vascular remodeling and regulation of the renal renin-angiotensin system. The evidence for TGFbeta activities during cardiovascular development and physiologic function will be given and areas which need further investigation will be discussed.     

Maturation of the angiotensin II cardiovascular response in the embryonic White Leghorn chicken (Gallus gallus)

Angiotensin II (Ang II) is an important regulator of cardiovascular function in adult vertebrates. Although its role in regulating the adult system has been extensively investigated, the cardiovascular response to Ang II in embryonic vertebrates is relatively unknown. We investigated the potential of Ang II as a regulator of cardiovascular function in embryonic chickens, which lack central nervous system control of cardiovascular function throughout the majority of incubation. The cardiovascular response to Ang II in embryonic chickens was investigated over the final 50% of their development. Ang II produced a dose-dependent increase in arterial pressure on each day of development studied, and the response increased in intensity as development progressed. The Ang II type-1 receptor nonspecific competitive peptide antagonist [Sar¹ ile⁸] Ang II blocked the cardiovascular response to subsequent injections of Ang II on day 21 only. The embryonic pressure response to Ang II (hypertension only) differed from that of adult chickens, in which initial hypotension is followed by hypertension. The constant level of gene expression for the Ang II receptor, in conjunction with an increasing pressure response to the peptide, suggests that two Ang II receptor subtypes are present during chicken development. Collectively, the data indicate that Ang II plays an important role in the cardiovascular development of chickens; however, its role in maintaining basal function requires further study.     

Development of cardiac form and function in ectothermic sauropsids

Evolutionary morphologists and physiologists have long recognized the phylogenetic significance of the ectothermic sauropsids. Sauropids have been classically considered to bridge between early tetrapods, ectotherms, and the evolution of endotherms. This transition has been associated with many modifications in cardiovascular form and function, which have changed dramatically during the course of vertebrate evolution. Most cardiovascular studies have focused upon adults, leaving the development of this critical system largely unexplored. In this essay, we attempt a synthesis of sauropsid cardiovascular development based on the limited literature and indicate fertile regions for future studies. Early morphological cardiovascular development, i.e., the basic formation of the tube heart and the major pulmonary and systemic vessels, is similar across tetrapods. Subsequent cardiac chamber development, however, varies considerably between developing chelonians, squamates, crocodilians, and birds, reflected in the diversity of adult ventricular structure across these taxa. The details of how these differences in morphology develop, including the molecular regulation of cardiac and vascular growth and differentiation, are still poorly understood. In terms of the functional maturation of the cardiovascular system, reflected in physiological mechanisms for regulating heart rate and cardiac output, recent work has illustrated that changes during ontogeny in parameters such as heart rate and arterial blood pressure are somewhat species‐dependent. However, there are commonalities, such as a β‐adrenergic receptor tone on the embryonic heart appearing prior to 60% of development. Differential gross morphological responses to environmental stressors (oxygen, hydration, temperature) have been investigated interspecifically, revealing that cardiac development is relatively plastic, especially, with respect to change in heart growth. Collectively, the data assembled here reflects the current limited morphological and physiological understanding of cardiovascular development in sauropsids and identifies key areas for future studies of this diverse vertebrate lineage. J. Morphol., 2009. © 2009 Wiley‐Liss, Inc.     

Obesity-associated activation of angiotensin and endothelin in the cardiovascular system

The renin-angiotensin system (RAS) and the endothelin system have been implicated in the pathogenesis of human cardiovascular and renal diseases, and inhibition of the RAS markedly improves morbidity and survival. Obesity in humans is associated with an increased risk for the development of hypertension, atherosclerosis and focal-segmental glomerulosclerosis, however the exact mechanisms underlying these pathologies in obese individuals are not known. This article discusses the clinical importance of obesity and the current evidence for local activation of the renin-angiotensin system and its interactions with the endothelin system in obesity and the cardiovascular pathologies associated with it.     

The state of the cardiovascular system in children aged 8–9 in the norm and in impairments of intellectual development

The specific features of the psychophysiological regulation of the cardiovascular system in healthy 8-to 9-year-old children and in children of the same age with impairments of intellectual development are considered. An analysis of the functional heart rhythm values after mental and physical exercise is given. The directions of correctional influence on the mechanisms of functional optimization of the cardiovascular system are outlined.     

MicroRNAs and cardiovascular diseases

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression. Recent studies have demonstrated that miRNAs are aberrantly expressed in the cardiovascular system under some pathological conditions. Gain- and loss-of-function studies using in vitro and in vivo models have revealed distinct roles for specific miRNAs in cardiovascular development and physiological function. The implications of miRNAs in cardiovascular disease have recently been recognized, representing the most rapidly evolving research field. In the present minireview, the current relevant findings on the role of miRNAs in cardiac diseases are updated and the target genes of these miRNAs are summarized.     

Protective effects of AMP‐activated protein kinase in the cardiovascular system

Cardiovascular diseases remain the leading cause of mortality worldwide. Recent studies of AMP-activated protein kinase (AMPK), a highly conserved sensor of cellular energy status, suggest that there might be therapeutic value in targeting the AMPK signaling pathway. AMPK is found in most mammalian tissues, including those of the cardiovascular system. As cardiovascular diseases are typically associated with blood flow occlusion and blood occlusion may induce rapid energy deficit, AMPK activation may occur during the early phase upon nutrient deprivation in cardiovascular organs. Therefore, investigation of AMPK in cardiovascular organs may help us to understand the pathophysiology of defence mechanisms in these organs. Recent studies have provided proof of concept for the idea that AMPK is protective in heart as well as in vascular endothelial and smooth muscle cells. Moreover, dysfunction of the AMPK signalling pathway is involved in the genesis and development of various cardiovascular diseases, including atherosclerosis, hypertension and stroke. The roles of AMPK in the cardiovascular system, as they are currently understood, will be presented in this review. The interaction between AMPK and other cardiovascular signalling pathways such as nitric oxide signalling is also discussed.     

Adipokines and the cardiovascular system: mechanisms mediating health and disease

This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.     

Participation of the cardiovascular neurons of the bulbar cardiovascular center in the adaptive reactions of the circulatory system during changes in the composition of inspired air

The experiments performed on rabbits have shown that with the inhalation of various gas mixtures the impulse activity of cardiovascular neurons in bulbar cardiovascular centre is changed. The most active are inserted cardiovascular neurons that are highly sensitive to O2 shortage and CO2 excess. It is believed that the experiments on Hering nerve severing indicate the possible development of reflex effects on hemodynamics during changes in inhaled gas composition produced from sinocarotid reflexogenic zone not only through bulbar respiratory neurons, but also through a system of inserted neurons of bulbar cardiovascular centre.     

Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse

We present here an analysis of cardiovascular and pharyngeal arch development in mouse embryos hypomorphic for Fgf8. Previously, we have described the generation of Fgf8 compound heterozygous (Fgf8(neo/-)) embryos. Although early analysis demonstrated that some of these embryos have abnormal left-right (LR) axis specification and cardiac looping reversals, the number and type of cardiac defects present at term suggested an additional role for Fgf8 in cardiovascular development. Most Fgf8(neo/-) mutant embryos survive to term with abnormal cardiovascular patterning, including outflow tract, arch artery and intracardiac defects. In addition, these mutants have hypoplastic pharyngeal arches, small or absent thymus and abnormal craniofacial development. Neural crest cells (NCCs) populate the pharyngeal arches and contribute to many structures of the face, neck and cardiovascular system, suggesting that Fgf8 may be required for NCC development. Fgf8 is expressed within the developing pharyngeal arch ectoderm and endoderm during NCC migration through the arches. Analysis of NCC development in Fgf8(neo/-) mutant embryos demonstrates that NCCs are specified and migrate, but undergo cell death in areas both adjacent and distal to where Fgf8 is normally expressed. This study defines the cardiovascular defects present in Fgf8 mutants and supports a role for Fgf8 in development of all the pharyngeal arches and in NCC survival.     

MicroRNA在靶向治疗缺血性心脏病中的研究进展

MicroRNA（MiRNA,miR）通过调节信使RNA（mRNA）的表达,广泛参与心血管系统细胞的增殖、迁移、分化、凋亡等病理生理过程,在心血管系统疾病的发生发展过程中起着重要的调控作用。越来越多的研究表明,针对缺血性心血管疾病的发病机制,通过特异性调节miRNA的活性,抑制相关蛋白的表达,对各种缺血性心脏病具有显著的治疗作用。但目前开发miRNA靶向治疗药物尚缺乏大规模的临床试验研究,其有效性和安全性需进一步证实。本文旨在综述MicroRNA在靶向治疗缺血性心脏病中的研究进展,以期为开发MiRNA靶向治疗药物治疗缺血性心脏病提供更多的理论依据。     

The role of some new factors in the pathophysiology of depression and cardiovascular disease: overview of recent research

Depressive disorders and cardiovascular disease are inter-connected by a whole range of pathophysiological mechanisms. Three biological mechanisms are fundamental: activation of the hypothalamus-hypohysis-adrenal axis with a subsequent increase in sympathetic-adrenal system activity, decrease in vagal tone with a decrease in heart rate variability, and alterations of thrombogenesis with increased platelet aggregability. Behavioural mechanisms and psycho-social factors are also integral to this common pathophysiology. Recently, research has focused mainly on studying various forms of stress, as well as changes and possibilities of influencing the autonomous vegetative system. Temporal aspects of the incidence and development of depressive episodes in relation to cardiovascular disease and subsequent cardiovascular morbidity and mortality are being studied, as well as general mortality risk factors. These findings are important for clinical practice. It is evident that in patients with untreated depressive disorder, the risk of developing cardiovascular disease is significantly higher than in patients suffering from a depressive disorder being treated with anti-depressants. From the data published so far, it may be surmised that depressive disorders in patients with cardiovascular disease may be reliably and safely treated with anti-depressants that act as inhibitors of serotonin re-uptake.     

Sex Differences in Hypertension: Contribution of the Renin–Angiotensin System

Numerous studies have shown that female human beings exhibit lower blood pressure levels over much of their life span compared with their age-matched counterparts. This sexual dimorphism is apparent in human beings as well as most, if not all, mammals. However, after the onset of menopause blood pressure levels in women increase and become similar to those in men, suggesting an important role of sex hormones in the regulation of blood pressure. The lower blood pressure levels in premenopausal women are associated with a lower risk of development and progression of cardiovascular disease and hypertension compared with age-matched men. This clear female advantage with respect to lower incidence of cardiovascular disease no longer exists after menopause, again highlighting the importance of sex hormones in the pathophysiology of cardiovascular disease in both men and women. In fact, both estrogens and androgens have been implicated in the development of cardiovascular disease and hypertension, with estrogens, in general, being protective and androgens being detrimental. Although the exact mechanisms by which sex hormones contribute to the regulation of cardiovascular function and blood pressure are still being investigated, there is increasing evidence that modulating the activity of locally active hormonal systems is one of the major mechanisms of sex hormone actions in target organs, including the vasculature and kidneys. Indeed, several studies have demonstrated the importance of the interaction between sex hormones and the renin–angiotensin system in regulating cardiovascular function and blood pressure. Furthermore, the differential effects of estrogens and androgens on the expression and activity of the components of the renin–angiotensin system could possibly explain the sex differences in blood pressure levels and the development and progression of cardiovascular disease and hypertension.     

NO as a mediator during the early development of the cardiovascular system in the zebrafish

As a general pattern innervation of the cardiovascular system appears late during development in vertebrate embryos, and cardiovascular control may be achieved by hormonal activity in early stages. However, very little is known about the onset of NO-responsiveness during development, which in adult vertebrates is known to play a key function in many physiological processes such as control of vascular tone, neurotransmission, macrophage activity, and angiogenesis. Analysis of the effect of NO on the cardiovascular system in zebrafish (Danio rerio) embryos and larvae revealed almost no effect on cardiac activity during chronic exposure to NO-producing chemicals, whereas vascular reactivity was observed in veins and arteries of the zebrafish in early developmental stages (5-6 days post fertilization). Chronic exposure also modified the development of the vascular system. The presence of an NO donor (sodium nitroprusside) did not change the patterning of the vascular bed, but it induced an earlier appearance of some blood vessels in the trunk region of the zebrafish larvae. The data reveal that NO plays an important role in the development of the cardiovascular system and in the ontogeny of the cardiovascular control system in fish.     

Chronophysiology of the cardiovascular system

The development of ambulatory blood pressure monitoring devices and the beat-by-beat measurement of heart rate have enabled it to be established that there are circadian rhythms in heart rate and blood pressure in subjects living normally. Investigations of these variables have led to quantification of their fall at night, and rapid rise on awakening and becoming active in the morning. These changes are of particular interest insofar as abnormalities in them are associated with cardiovascular problems and morbidity in patients and also act as risk factors in otherwise healthy individuals. It has also been shown that there are many other variables of the cardiovascular system. The causes of the circadian rhythms in heart rate and blood pressure are outlined, with particular stress upon the role of the autonomic nervous system, as assessed from low- and high-frequency components of the variation in heart rate measured beat-by-beat. Activity increases blood pressure, but there is evidence that this “reactivity” varies with time of day, and this also might be related to cardiovascular morbidity. Based upon data from several sources, including night work, resting subjects and bed-ridden patients, it is concluded that the contribution of the “body clock” to producing the circadian rhythm in heart rate and blood pressure is relatively small. A bias towards an exogenous cause applies also to most other circadian rhythms in the cardiovascular system. Knowledge of circadian rhythmicity in cardiovascular system, together with an understanding of its causes, provides a rationale for advice to reduce cardiovascular risk and to assess the efficacy of therapies.