The Mechanism Of EPCs Homing And As A Delivery System For AS Plaque In LSS

Cardiovascular disease is the common diseases affecting human health.And Coronary heart disease is the main fatal and disabling disease,bringing a serious economic and burden on patient and the community.Coronary heart disease could cause myocardial ischemia by coronary atherosclerotic plaque instability and lumen stenosis.Because,pathology and development mechanism of coronary artery plaque and unstable state are not clear,the treatment and reverse atherosclerotic plaque has become a major challenge.Revealing the molecular mechanism and developing a appropriate treatment for atherosclerotic plaque destabilization of coronary heart disease has become research focus.At present,the atherosclerosis(AS)is considered as a chronic inflammatory of vascular involvedmulticellular multiple factors and cells.Many hypotheses of the atherosclerosis pathology was included: endothelial injury and lipid infiltration doctrine,the doctrine of oxidation,thrombosis doctrine,the doctrine of inflammation,injury response theory,monoclonal theory,homocysteine theory,arginine,science and shear stress theory.From the large number patients with coronary heart disease,pathological anatomy suggest that atherosclerotic lesions may easily occurr in the vascular bifurcation,and the opening bend,showing a high incidence of local characteristics.It is difficult to explain by systemic factors.Hemodynamic characteristics of these parts is different to the others parts vessle,which show us: abnormal hemodynamic of the artery may be an improtant risk factor for development of atherosclerosis.How to affect atherosclerosis pathological process by abnormal hemodynamic of coronary atherosclerosis.(Scientific question one).Artery could adapt to the abormal state of blood flow to increase the adaptive protecting response.Vascular endothelial cell is most important and most direct response element cells for abnormal blood flow status.How to screen this protective response and find a protective molecule,which could reverse the atherosclerotic plaque and become a therapeutic target molecule(Scientific question two)Flow of coronary blood is very fast,how to targeted deliver therapeutic molecules is an important problem,and developing a suitable delivery system is an improtant engineering problems(Scientific question three)A lot of reports of coronary atherosclerosis pathology show that,abnormal hemodynamics coud serious effect the function of endothelial cell function and inflammation,intimal hyperplasia,and mediate endothelial progenitor cells,immune cells homing to the atherosclerotic plaques.It is improtant to process of atherosclerotic plaques.Microarray is a common tool to study the overall effection on cell with a high-throughput advantage,but many others factors could effect the analytical.Cell self-assembly is an improtant tool to load drug molecules on the cell surface,use of positive and negative charges attract each other,We assume " Protection factor loaded EPCs could been a therapy of reversal of atherosclerotic plaque using layer self-assembly and homing of atherosclerotic tissue "Based on the above background,three important scientific questions and hypothesis,we would carry three aspects in-depth study asfollowing.First part,The mechanism of atherosclerosis and EPC homing led by abnormal hemodynamicsLSS could promote EPCs homing into the plaque.Possible mechanisms are(a)fluid shear stress may stimulate EPCs mobilization induced plasma platelet adenosine release by regulation.(B)LSS can cause endothelial cell damage,increased platelet activation and adhesion molecules expression,thereby inducing platelet aggregation in the LSS area(C)Fluid SDF-1 play an improtant role in EPCs homing plaque platele and expression of SDF-1 on EPCs led by shear stress-induced stimulationSecond part,Screening protective molecular and response adaptation resisted atherosclerosis led by abnormal hemodynamicsReal-time RT-PCR chip revealed that expression of VEGF,PSGL-1,TNC,Thbs4,SOD-1,TNF AIP,PPAR?,PPAR?,Apo A1,bcl2a1 a was significantly different treated by different hemodynamics.Expression of LSS(proximal)was significantly higher than the OSS field(distal).Red figures show more than 1.5 times the value.However,VEGF and VWF increased by two times,which is the main trigger factor homing of EPCs.Expression of PSGL-1,TNC,as well as show a significant increase.Thbs4 promotes platelet adhesion and activation.At the same time,real-time quantitative PCR results showed that in a large area of 3.97-fold SDF-1 expression than the control area.SDF-1 expression of the OSS field of 1.24 times.We analysis these differences of transcription related to coronary atherosclerosis,cell adhesion,homing,endometrial,homeostasis of inflammation.On the other hand,the differences of transcription proved an result that unstable coronary blood flow caused by atherosclerotic plaque could promote the pathological progression of coronary atherosclerosis and plaque instability of fibrous cap for broken.Transcriptional chip of ApoE-/-and in vitro relust show that netrin-1 can be an important protective molecules of adaptation response.Many repots suggested that netrin-1was an improtant factor to promote axonal growth,growth of new blood vessels and promotion of germination and newborn.Netrin-1 have an effection on vascular tissue and nerve tissue.In vitro,studies revealed that Netrin-1 can stimulate proliferation,migration of EPCs and differentiation into capillary endothelial cells to angiogenesis.netrin-1 play an important role in the pathological process of atherosclerosis,intima inflammation and immune homeostasis.Third part,Construction of netrin-1loaded,gelatin / hyaluronic acid self-assembled EPCs delivery systemWe successfully constructed a Netrin-1 loaded,gelatin / hyaluronic acid self-assembled EPCs delivery vehicle.And,the experiment proved that the delivery system of EPCs has a certain targeting atherogenic by inflammatory environment.This shows that Netrin-1 loaded,gelatin / hyaluronic acid self-assembled EPCs could be a very promising treatment strategies targeted delivery of drugs to the unstable plaque.Endothelial progenitor cells is a very promising anti-coronary drug biological carrier,which has a good biocompatibility,relatived to other common drug delivery systems synthesised by chemical method.Efficiency of Endothelial progenitor cell as drug carriers homing to atherosclerotic is higher.Netrin-1 loaded,gelatin / hyaluronic acid self-assembled EPCs delivery system could effective migrate into atherosclerotic plaques in the intimal layer to achieve sustained release drug molecules.