Research Area

Cardiovascular System Development

Cardiovascular system development overview

Cardiovascular disease is one of the most serious diseases that endanger human life and health in China and the whole world. Its prevalence and mortality rank first among all kinds of diseases. Cardiovascular diseases include hypertension, atherosclerosis, stroke and myocardial infarction. These cardiovascular diseases have a common pathogenesis and basic pathological processes, including cardiovascular cell migration, hypertrophy, proliferation, and apoptosis. It has a change in cell phenotype, morphological structure and function, that is, cardiovascular system development occurs. Cardiovascular system development refers to the changes in morphological structure and function of blood vessels in response to changes in the internal and external environment during growth, development, aging, and disease. The cardiovascular system development of cardiovascular disease is essentially response of the body to the homeostasis imbalance of the cardiovascular system caused by different pathogenic factors. The material basis for maintaining the homeostasis of the cardiovascular system is a cardiovascular active substance that functions as a regulator. Cardiovascular active substances include proteins, peptides, enzymes, growth factors, cytokines, adhesion molecules, and information transfer molecules that regulate cardiovascular growth, development, morphological structure, and functional activities. The study of cardiovascular active substances is also one of the most active and important frontiers in life science research.

Cardiovascular system development research status

What are the key factors that cause mechanical signals in the development of a cardiovascular system to cause different biological effects of vascular wall cells? This is a key scientific issue in the study of vascular mechanical biology. Proteomics studies all proteins and their interactions expressed by the genome of a cell or tissue under specific time or environmental conditions. At the same time, because protein is not only a target molecule for a variety of virulence factors but also a target for most drugs and even direct drugs, proteomics is still a powerful technology platform for finding drug targets in recent years. In vitro, a vascular external physiological pulsation stress culture system was established for the first time, and the in vitro culture of intact blood vessels under different mechanical conditions was realized. The system was combined with biomechanics, proteomics, and bioinformatics, and it was first developed at home and abroad. Research work on the effects of mechanical stress on vascular proteomics. The differential protein expression profiles of blood vessels under different mechanical conditions were analyzed. More than 60 differentially expressed proteins were screened and the role of proteins such as Rho-GDI alpha and HSP27 in stress-induced cardiovascular development was explored. This research introduces new proteomics technology into the field of mechanical biology research, explores the molecular mechanism of low shear stress-induced cardiovascular system development, and provides a search for cardiovascular disease pathogenesis and cardiovascular system development drug therapy targeting. A new perspective of mechanical biology embodies the innovative features of interdisciplinary integration. Vascular smooth muscle cells, as one of the main cellular components of the vascular wall, transform from a contractile phenotype to a synthetic phenotype, which is an important link leading to the development of cardiovascular system. In vivoVSMCs are primarily affected by mechanical tensile stresses generated by pulsatile blood flow. The periodic tensile strain loading consists of three important parameters: frequency, amplitude and time. The effects of cyclic strain loading amplitude and time on cell function have been reported at home and abroad, but the effect of loading frequency on the function of VSMCs is still unclear. Clinically, heart rate diversity and instability are thought to be closely related to the development of cardiovascular disease. Therefore, to study the effect of mechanical strain on the function of VSMCs, the important regulation of the frequency of tensile strain should be considered. We applied the flexcell cell strain loading system to apply 10% periodic tensile strain to the rat VSMCs culturedin vitro at frequencies of 0.5 Hz, 1 Hz, and 2 Hz, respectively. The loading time was 24 h, at 0 Hz, ie no loading frequency, continuous loading 10 % strain of VSMCs was used as a control group. Detecting changes in morphology and arrangement of VSMCs; Changes in mRNA and protein levels of VSMCs phenotype markers alpha-actin, myosin heavy chain, actin-related protein SM22α, and tunning proteins; inhibitors or RNA interference block the activity of possible signal-regulating molecules or expression, including p38, extracellular signal-regulated kinase 1/2, protein kinase B (PKB/Akt) and Rho-guanylic acid dissociation inhibitor, was studied by cyclic strain loading at different frequencies forin vitro cultured VSMCs alignment. The results show that the periodic strain frequency is an important regulatory factor for the arrangement of VSMCs. The VSMCs should have the most sensitive frequency in a certain range. The outside-in and inside-out signaling pathways of the cells are involved in the signal transduction process of VSMCs aligning with different strains. The complete cytoskeletal microfilament system may be the key structure for sensing the strain frequency signal. Different frequency tensile strains can induce the transformation of synthetic phenotypes of VSMCs into contractile phenotypesin vitro, with the strongest mechanical stretch at 1 Hz, which is closely related to p38 signaling pathway and Rho-GDI alpha regulatory factor. Vascular endothelial cells (ECs) and VSMCs are the major cellular components of the vessel wall. The luminal surface of ECs is in direct contact with the blood flow and is subjected to fluid shear stress. The basal plane is adjacent to VSMCs. The change of ECs function directly affects the function of VSMCs. Abnormal migration behavior of VSMCs is one of the common pathological manifestations of common vascular lesions such as atherosclerosis, angioplasty and in-stent restenosis, and occlusion after venous bypass grafting. VSMCs migrate from the lining of the blood vessels to the intima, which in turn proliferate and secrete ECM to participate in the formation of neointima. A variety of biochemical and physical stimuli including mechanical stress and growth factors affect the migration of VSMCs. To explore the mechanisms that influence and regulate the migration of VSMCs have important theoretical and practical significance for understanding the pathogenesis of cardiovascular diseases. Foreign scholars have established a variety of joint culture models to study the interaction of VSMCs and ECs in the same system. The flow chamber system in which ECs was combined with VSMCs was used to control the fluid as laminar flow with a shear stress of 15 dyne/cm2. Transwell method was used to detect the change of migration ability of VSMCs under different conditions, and the change of Akt phosphorylation level in VSMCs was observed. The role of a PI3K-Akt signaling pathway in the migration of VSMCs under shear stress combined culture conditions. The results showed that static combination of VSMCs and ECs could significantly promote the migration of VSMCs. The direct (or almost direct) interaction of ECs and VSMCs plays an important role in the migration of VSMCs; while the physiological size of the shear stress acts as a stabilizing factor for vascular ECs, which can inhibit the migration of VSMCs by ECs, thereby protecting the vessel wall. This is related to the PI3K/Akt signaling pathway. The VSMCs and ECs co-culture models were also used to study the mechanism of cell-cell communication between ECs and VSMCs under shear stress. Studies have shown that low shear stress directly affects ECs, increasing its synthesis and release of PDGF-BB and TGFβ, while increased PDGF-BB and TGFβ1 have different biological functions. PDGF-BB released by ECs is involved in the proliferation and migration of ECs and the regulation of various signal transduction molecules in cells. At the same time, PDGF-BB and TGFβ1 synthesis and cell proliferation and migration are regulated by paracrine effects in adjacent VSMCs. A variety of intracellular signal transduction molecules are activated. The release of TGFβ1 by ECs is involved in the regulation of ECs' own proliferation and migration and has no significant effect on VSMCs. In addition, PDGF-BB and TGFβ1 synthesized by VSMCs can regulate ECs function through paracrine feedback.

Cardiovascular system development clinical applications

Although the mechanism of localization of vascular intimal hyperplasia after atherosclerosis, thrombosis and the arterial bypass is still not very clear, regardless of its mechanism, the scientific community generally believes that the location of the vessel geometry changes rapidly (including the bridge). The flow separation and vortex zone caused by the disturbance of blood flow is the root cause of the local phenomenon of these diseases. It is important to study the local pathogenesis of cardiovascular disease. When the mechanism is not fully understood, it is more desirable to use the fact that the local phenomenon of these diseases is related to the blood flow field. Changes in the local shape of the vessel or the specific configuration of the interventional instrument during cardiovascular repair and interventional procedures can cause changes in local hemodynamic properties. The changes in local hemodynamic characteristics are closely related to vascular lesions such as atherosclerosis and intimal hyperplasia. Therefore, in the planning of cardiovascular repair and interventional surgery, it is necessary to plan, predict the hemodynamic risk caused by surgery, adjust the surgical planning, and optimize the design of interventional instruments. The following is a review of the research progress of hemodynamic optimization in the planning of vascular bypass graft surgery and interventional treatment planning at the coronary bifurcation. The vascular occlusion caused by atherosclerosis, acute thrombosis, and other causes is the main cause of severe cardiovascular and cerebrovascular diseases such as myocardial infarction and stroke. At present, the surgical method commonly used in the medical field is to use an arterial bypass or reconstructive surgery using autologous blood vessels or artificial blood vessels in other parts of the patient. Arterial bypass surgery uses another blood vessel to form a bypass between the anterior and posterior ends of the original vascular occlusion site, so that blood can be smoothly supplied to the downstream through this reconstituted bypass. However, although the effect of arterial bypass surgery is obvious, the vascular re-occlusion is often caused by the intimal hyperplasia in the later stage of surgery. Especially for vascular bypass surgery of small and medium blood vessels, intimal hyperplasia has become a major cause of failure in the later stages of surgery. Statistics show that moderate blood vessels, such as femoral-popliteal bypass grafting, femoral-tibia bypass grafting, can cause a surgical failure rate of 70% to 85% due to restenosis after 5 years. The problem of intimal hyperplasia after bypass surgery has long plagued the medical community. Intimal hyperplasia after arterial bypass surgery occurs mainly at the end of the bypass vessel and the end of the bridged vessel. Intimal hyperplasia is mainly caused by the proliferation of smooth muscle cells, fibroblasts and infiltration into neointima. Intimal hyperplasia after vascular bypass surgery has many similarities in pathological morphology with atherosclerosis in the later stages. Coincidentally, many atherogenic factors, such as smoking, diabetes, etc., also accelerate the development of intimal hyperplasia. It is worth noting that the location of intimal hyperplasia after arterial bypass surgery has a certain regularity. Vascular bypass surgery uses side-to-end and end-to-side sutures. Although intimal hyperplasia can occur simultaneously in the upper and lower anastomosis segments of the implanted blood vessels, for the bypass surgery such as side-to-end and end-to-side, the intimal hyperplasia produced downstream is much higher than upstream. It is also the main part of the failure that leads to late surgery. For the endometrial hyperplasia at the end-to-side, there are two more prone sites: the bypass vessel and the bypass of the bypass vessel and the bottom of the grafted vessel, and the latter is the most severe site of intimal hyperplasia. Intimal hyperplasia at the suture is primarily due to vascular healing and vascular modeling due to physical trauma and compliance mismatch. The reason for the intimal hyperplasia at the position of the underside of the bypass vessel is not clear. In response to this problem, Deng et al. proposed an eccentric bypass surgery planning program. The flow field display and hemodynamic numerical simulations show that this kind of eccentric bridging can make the blood flow form a clear swirling flow at the bridged anastomosis site, effectively improving the blood flow field there. The results of animal experiments show that the thickness of the endocardium at the end anastomosis site of the vascular bypass is smaller than that of common vessels and the endometrial thickness of traditional bypass vessels, which proves the rationality of this eccentric bypass surgery planning from the perspective of animal experiments. At present, the research on interventional treatment of coronary bifurcation mainly focuses on how to achieve accurate implantation and effective connection of the bifurcation stent. How to improve the intimal hyperplasia and thrombus adhesion by improving the drug composition of the drug-eluting stent. So far, no one has systematically studied the problem of low patency rate in the late stage of interventional treatment of coronary artery bifurcation from the perspective of hemodynamics. Therefore, an in-depth study from the hemodynamics perspective can provide a basis for the design of special stents and interventional procedures for coronary bifurcation with good hemodynamic properties. This research will have important theoretical value and clinical guiding significance for improving the late patency rate of interventional therapy in coronary artery bifurcation.


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