Studies On Salvianolic Acid A Inhibiting Microvascular Remodeling In Spontaneously Hypertensive Rats And Spatiotemporal Changes Of Monocytes/Macrophages In Aortic Dissection

Danshen is the dried root of Salvia miltiorrhiza Bge. It can activate blood to eleminate stasis, induce menstruation to relieve menalgia, relieve palpitation to stop irritation, and cool blood syndromes away. Modern medical researches show that Danshen can relax coronary artery, improve microcirculation, inhibit platelet aggregation/adhesion, suppress thrombus formation and prevent myocardial ischemia-reperfusion injury. Therefore, Danshen is often used alone or combinated with other herbal in the treatment for cardiovascular diseases. Polyphenol acids are the main water soluble extracts in Salvia miltiorrhiza. In particular, salvianolic acid A (SalA) holds the good physiological activities. Our study mainly focus on two aspects:the first one is to clarify the protective effect of SalA on microvascular remodeling induced by hypertension; the other one is to explore the pathogenesis of aortic dissection and lay a foundation for evaluating the therapeutic effect of SalA on aortic dissection.At present, there are a lot of antihypertensive drugs, which can significantly reduce the symptoms of hypertension. But these antihypertensive drugs can not solve the microvascular remodeling and target organ damage caused by hypertension. Therefore, it is very important to develop new medicine for microvascular remodeling induced by hypertension. In our study, spontaneously hypertensive rats fed with high salt diet was used to evaluate the effect of SalA on microvascular remodeling induced by hypertension. Our results showed that SalA can significantly inhibit the retinal microvascular remodeling, decrease cardiac microvascular fibrosis, protect the ultrastructure of mesenteric microvascular endothelial cells, improve the endothelial dependent relaxation function and ameliorate complication of kidney. Based on the beneficial effect of SalA on the endothelial dependent relaxation of mesenteric microvessels in vivo, we further evluated the beneficial effect of SalA on endothelial cell function directly in vitro. We stimulated endothelial cells with lipopolysaccharide (LPS) to build the model of endothelial cell dysfunction. Our results showed that SalA can inhibit endothelial cell migration, decrease of endothelial transendothelial electrical resistance and increase of monolayer endothelial cells permeability. The results showed SalA could significantly inhibit microvascular remodeling induced by hypertension, normalize endothelial dysfunction and relieve the damage of target organ. This study suggested that SalA was a great active ingredient of Danshen in inhibiting microvascular remodeling.It is well known that the aorta is composed of three layers including intima, media and adventitia. Aortic dissection occurs with spontaneously torn at the intima or media, extends along aortic wall, and eventually leads to aortic rupture under the blood flow shear stress. Aortic rupture often results in bleeding and death. Therefore, aortic dissection is one kind of the diseases with the highest mortality among cardiovascular disease. At present, the pathogenesis of aortic dissection is poorly understood. There are no effective drugs for aortic dissection in clinical treatment. Therefore, it is urgent to explore the mechanism of aortic dissection. Our previous studies have found that inflammatory cells increased significant at the early stage in the patients with aortic dissection. We hope to build an animal model of aortic dissection to investigate the inflammatory response before the the formation of this disease, which provides a breakthrough for disease prevention and control. The mice were treated with β-aminopropionitrile to induce aortic dissection. We evaluated the incidence of aortic dissection, the number of inflammatory cells in peripheral blood and inflammatory cell infiltration on the aortic wall in early (10 days), middle (20 days) and late (30 days) stages, respectively. The results showed that the number of monocytes in peripheral blood, the number of macrophages that infiltrated into aortic wall, and the expression of MMP-12 protein increased with the progression of the disease. These findings suggested that the development of inflammation might be one of the important factors for promoting the formation of aortic dissection. There are a variety of active components that can inhibit monocyte/macrophage infiltration in Danshen. SalA extracted from Danshen was also a broad-spectrum MMP inhibitor. This study elucidates the possible pathogenesis of aortic dissection and lays a foundation for finding active ingredients of Danshen to fight this disease.To sum up, hypertension can lead to microvascular remodeling and eventually the damage of target organs. SalA can significantly improve the function of vascular endothelial cells, inhibit the microvascular remodeling and reduce the target organ damage induced by hypertension. Moreover, we successfully built the animal model of aortic dissection and investigated the role of the inflammatory cells in the progression of aortic dissection in this model. We detected macrophages infiltration and matrix metalloproteinase-12 that at the early stage of aortic lesion. In addition, we also found the damage of elastic fiber became more serious with the number of macrophages and the expression of metalloproteinase-12 increasing in aortic tissue. These findings provided a good starting point for SalA treatment on dissection in our futher study.