Endothelium is the primary regulator of vascular tension and endothelial function refers to the normal diastolic response of blood vessels and maintenance of blood flow through its production of vasoactive substances in response to endothelium-dependent stimuli. Endothelial dysfunction is mainly manifested as endothelium-dependent diastolic dysfunction. In recent years, in-depth studies on the process of atherosclerosis formation have found that endothelial dysfunction is its initiating and promoting factor. Early prevention or slowing down the development of endothelial dysfunction and long-term protection of endothelium has become a new hot spot and research direction for prevention and treatment of cardiovascular diseases. The shift from treatment-based to prevention-based is a new medical concept of milestone status, and we are eager to find a safe and effective endothelial protection drug with a wide range of application to slow down the development of cardiovascular diseases. Among the existing six major first-line antihypertensive drugs, ACEI is the first in terms of improving endothelial function. From 1996, when Mancini GB et al [1] first confirmed the improvement of endothelial dysfunction by ACEI in a clinical trial, to the latest large-scale clinical trial (European Perindopril Study for the Reduction of Cardiac Events in Stable Coronary Artery Disease, EUROPA), which fully confirmed its significant superiority over ARB class drugs in protecting endothelial function. Over the past decade, research on the relationship between ACEI and endothelial function has gradually intensified, and several possible mechanisms have been identified to further guide clinical use. In this paper, we review this decade of research, summarize the main mechanisms of ACEI protection of vascular endothelium, and explore its efficacy. (1) ACEI increases the expression and activity of endothelial nitric oxide synthase (eNOS) Studies have demonstrated that NO produced by endothelial nitric oxide synthase (eNOS) mediates a variety of cardiovascular protective effects. NO is converted from L-arginine in the presence of eNOS.NO is released by elevated blood flow (leading to increased endothelial stress stimulation) and stimulation by bradykinin, hemolysin, acetylcholine and a range of circulating factors.NO activates guanylate cyclase by acting on the iron atom in guanylate cyclase, elevates intracellular cGMP levels, decreases intracellular calcium in smooth muscle, and causes Animal experiments by Xiao-Ping Yang et al. 1999 showed that eNOS-/- knockout mice had a significantly lower therapeutic response to ACEI during episodes of myocardial ischemia compared to normal mice, suggesting that ACEI promotes vasodilation by affecting eNOS function and thereby increasing NO production. shinichi Kanno et al. 2001 obtained similar results in mice with pulmonary hypertension. a study published by H. Morawietz et al. 2006 selected patients who were to undergo coronary artery bypass surgery and divided them into two groups according to whether they were previously taking ACEI or not. myocardial biopsies were taken during coronary artery bypass surgery to measure the expression of eNOS mRNA in cells. It was revealed that in patients with coronary artery disease and heart failure, eNOS mRNA expression was significantly higher in patients in the ACEI-treated group compared to the control group. It directly demonstrated that ACEI can promote the expression and activity of eNOS in vivo. (2) ACEI reduces bradykinin degradation Bradykinin is a vasoactive substance produced from kininogen by the action of kinin-releasing enzymes. In vivo, bradykinin is quickly degraded (half-life less than 30s), and because of its short half-life, it is generally believed that it is synthesized in tissues and plays a local effect. Bradykinin binding to bradykinin B2 receptor (BKB2R) can promote the release of NO and prostacyclin from endothelial cells, causing vasodilation.In a study published by James V. Gainer et al [6] in 1999, a test group and a control group were established in a hypertensive population and a normotensive population. For the test group, a bradykinin antagonist was given followed by an ACEI (captopril); for the control group, only an ACEI was given. results in both the hypertensive and normotensive groups showed that the bradykinin antagonist significantly attenuated the antihypertensive effect of the ACEI. This suggests that part of the antihypertensive effect of ACEI is mediated by bradykinin. It has been shown that angiotensin-converting enzyme inhibitor (ACE) is one of the most important bradykinin enzymes, which has a high affinity for bradykinin and can degrade it. release and enhance the diastolic function of vascular endothelium. (3) A few notes on (1) and (2) Both of the above pathways act through NO, so we have the question whether they are on the same pathway. That is, does ACEI promote the activity of eNOS by reducing bradykinin degradation and thus lead to increased NO release? Regarding the first pathway, no studies have explored whether ACEI can directly cause upregulation of eNOS expression in bradykinin-deficient animals. Regarding the second pathway, M. A. Hassan Talukder et al. found in a study published in 2004 [8] that bradykinin also induced coronary artery dilation in eNOS-deficient mice in eNOS-/-, but that neurocyte carbon monoxide synthase (nNOS) inhibitors and guanylate cyclase inhibitors greatly attenuated the eNOS-/- vasodilation in eNOS-/- mice bradykinin’s vasodilating effect, suggesting that bradykinin protects vascular endothelial function through multiple pathways. 2, ACEI inhibits angiotensin II (Ang II)-dependent endothelial oxidative stress One of the main mechanisms by which Ang II impairs endothelial function is through the activation of the NAD(P)H oxidase system, which causes superoxide radicals to be generated in endothelial cells and vascular smooth muscle cells. These superoxide radicals react with NO at a rapid rate and are capable of directly deactivating NO and producing peroxynitrite. Further, peroxynitrite and other oxidants are able to oxidize tetrahydrobiopterin, which is the main cofactor of eNOS, disrupting the NO production pathway. Disintegrated eNOS also further exacerbates oxidative stress in the endothelium, leading to inactivation of DDAH, the degrading enzyme of the eNOS inhibitor ADMA. This vicious cycle greatly disrupts NO-mediated endothelial function. Obviously, ACEI is able to reduce Ang II production by inhibiting ACE, which also breaks this vicious cycle chain and protects endothelial function. In recent years, it has been suggested that the ratio of bradykinin to angiotensin II is a measure of efficacy, and that an increase in its value leads to an increase in vascular eNOS activity, which is important for the prevention of cardiovascular events. Studies have shown that ACEI (perindopril) can significantly increase the bradykinin/Ang II ratio in vascular wall tissues and play a role in vascular protection. 3, ACEI promotes the production of endothelin (ET) ET as a vascular endothelium-derived contractile factor is an injury-causing factor produced by the body under ischemia and hypoxia, and excessive levels of ET-1 are often detected in hypertensive atherosclerotic patients. As early as 1996, it was shown that ACEI significantly reduced ET levels and alleviated endothelial-mediated diastolic dysfunction in normal subjects or diabetic patients. The mechanism may be that ACEI reduces the production of Ang II, an inhibitor of ET, which promotes the production and release of ET. In recent years, most domestic clinical trials investigating the relationship between ACEI and vascular endothelial function have used ET as an indicator of efficacy. 2008, a study used benazepril to treat patients with chronic heart failure, and after 10 weeks of treatment, ET levels in patients were significantly reduced. 2009, a study used fosinopril to treat elderly patients with coronary artery disease, and after 8 months of treatment, serum ET-1 concentrations in patients were There was a significant reduction in serum ET-1 concentrations and a significant improvement in brachial endothelial pressure-dependent diastolic response after 8 months of treatment. These studies demonstrate that ACEI can improve vascular endothelial function by reducing ET concentrations. 4, ACEI promotes the release of Endothelium-Derived Hyperpolarizing Factor (EDHF) Several studies in recent years have simultaneously demonstrated that in the presence of NO and prostacyclin inhibition, endothelial cells are able to maintain intravascular homeostasis through another substance, which is EDHF. , EDHF is a substance or electrical signal produced and released by endothelial cells that hyperpolarizes vascular smooth muscle cells, causing them to diastole and dilate vessel diameter.EDHF has been used as one of the important indicators of endothelial function. Studies have shown that the vasodilating effect of EDHF correlates with arterial diameter and is significantly stronger in small than large arteries. It is suggested that EDHF may play an important role in organ blood flow regulation and peripheral vascular resistance regulation. In the case of vascular endothelial injury and abnormal NO regulation, EDHF may play a compensatory regulatory role. animal experiments by Kenichi Goto et al. gave ACEI (enalapril) to treatment group 1 mice, hydrazinpyridazine hydrochloride and hydrochlorothiazide to treatment group 2, and a blank control. The results showed that the hypotensive effects of treatment group 1 and treatment group 2 were comparable, but the membrane potential measured by electrophysiological experiments revealed that the EDHF-mediated hyperpolarization initiated by acetylcholine was significantly stronger in treatment group 1 than in treatment group 2 and the control group. This suggests that ACEI promotes the release of EDHF and protects endothelial function, and that this effect is independent of the hypotensive effect. The mechanism of this is not clear, but several interesting properties of EDHF are now found to be noteworthy. Animal experiments [18] have shown significant sex differences in the compensatory regulatory effects of EDHF. EDHF-mediated diastolic effects in small arteries were observed in mice deficient in eNOS and COX-1 (cyclooxygenase): in females, EDHF was fully compensated and the animals’ mean arterial pressure was unaffected, whereas in males, the compensatory results were unsatisfactory and the animals developed hypertension. Similar results were obtained in later studies on mesenteric and caudal arteries in mice and genital arteries in rabbits, suggesting that there may be gender differences in endothelial-mediated vasodilation, with EDHF playing a major role in females and NO playing a major role in males. Animal studies have also shown that the effect of EDHF diminishes with age, suggesting that it may be associated with endothelial damage and a predilection for hypertension in the elderly. This arterial diameter-related, sex-related, and age-related study of EDHF regulation is still in its infancy, and numerous experiments have been conducted to explore itself, with a recent study in 2009 [20] suggesting the possibility that S-nitrosothiols are the enigmatic EDHF, but more evidence is lacking. Meanwhile, experiments on EDHF are still at the stage of animal experiments, and a more in-depth exploration of EDHF is believed to give us new insights in the protection of endothelial function. 5, ACEI promotes Ang-(1-7) production Recent studies have identified a new branch of the RAA system, the ACE2-Ang-(1-7)-Mas axis. ang-(1-7) is mainly generated by hydrolysis of AngI or Ang II by ACE2 (a homolog of ACE) and degraded to inactive Ang-(1-5) by ACE. mas is a vascular A study published by Mariana B.L et al [23] in 2007 found that short-term injection of AVE0991 (a non-peptide analogue of Ang-(1-7)) into normotensive mice significantly enhanced the hypotensive effect of intra-arterial bradykinin, but this bradykinin-mediated hypotensive effect of AVE0991 However, this bradykinin-mediated hypotensive effect of AVE0991 was completely blocked by an eNOS inhibitor (L-NAME) or Mas receptor blocker (A-779), and in vitro experiments also showed that the hypotensive process of AVE0991 involved the release of NO. It can be speculated that the mechanism of action of Ang-(1-7) to promote the hypotensive and diastolic effect of bradykinin includes specific binding of Mas receptors and eNOS-mediated NO release. ACEI inhibits ACE, increases the concentration of Ang I, the main raw material for Ang-(1-7) production, and promotes the activity of ACE2, which increases Ang-(1-7) production, while decreasing Ang-(1-7) production by inhibiting ACE reduces the degradation of Ang-(1-7), which together elevates Ang-(1-7) and promotes its endothelial-mediated vasodilatory function. Studies have shown that ACEI use can increase the amount of Ang-(1-7) by as much as 25-50 fold. The mechanism of Ang-(1-7) regulation under physiological conditions is currently unclear, and further studies have the potential to make it a new target for cardiovascular disease treatment. 6, ACEI anti-endothelial cell apoptosis and promote their regeneration (1) ACEI anti-endothelial cell apoptosis Endothelial cells undergo a cycle of apoptosis and regeneration every 3 months, and once this balance of apoptosis and regeneration is broken, the integrity of the vascular endothelium is disrupted. One of the sub-studies of EUROPA, the PERTINENT study, looked at the effect of perindopril treatment on endothelial cell apoptosis. The results showed that treatment with perindopril 8 mg/d for 1 year reduced endothelial apoptosis by 31% (p<0.05), demonstrating that it significantly reduced the abnormally high level of endothelial apoptosis in patients with coronary artery disease. The mechanism is believed to be that perindopril inhibits the production of pro-apoptotic factor AngII and tumor necrosis factor TNF-α, and increases the level of anti-apoptotic factor bradykinin to restore the balance of AngII and BK levels. (2) ACEI increases the number and improves the function of endothelial progenitor cells (EPCs) Endothelial progenitor cells are primitive cells that originate from bone marrow, and under the action of physiological or pathological factors, EPCs in bone marrow enter the peripheral blood circulation and can be directed to differentiate into mature endothelial cells under certain conditions. It has been demonstrated that 25% of endothelial cells in neovascularization are differentiated from EPCs, and vascular repair partly depends on the adhesion, aggregation, value-added, and differentiation of endothelial progenitor cells in blood at the site of injury to form new vascular endothelium. Therefore, EPCs have an important role in repairing endothelial function, promoting re-endothelialization, and delaying atherosclerosis formation. In addition, EPCs can promote the generation of eNOS and enhance endothelial function under ischemic conditions. in the EUROPA study, patients with myocardial infarction treated with perindopril 8 mg/d for 7-10 days showed a significant increase in the number of EPCs, demonstrating the role of ACEI in promoting the generation of EPCs and promoting endothelial cell regeneration. In contrast, in the same study, treatment with ARB did not result in an increase in EPCs. In conclusion, vascular endothelial dysfunction may be an important cause of imbalance in the circulating internal environment, and the mechanism by which ACEI protects vascular endothelial function is mainly through the six major pathways mentioned above. In the complex internal environment, the pathways are not independent of each other but affect each other. For example, bradykinin can affect the release of NO, which is also involved in the process of Ang-(1-7) action; the anti-endothelial apoptosis effect also involves the regulation of Ang II and bradykinin levels. The artificial division of the 6 pathways is only to help understanding and summary. It is also worth mentioning that the degree of action of all classes of ACEI in improving vascular endothelial function varies widely, and studies have shown that ACEIs with high affinity have stronger effects than ACEIs with low affinity, suggesting that as the current drug of choice for improving endothelial function, different drugs under the ACEI major class should be studied differently, and their new indications and new uses need to be further explored. It can be foreseen that ACEI will have a great role in protecting vascular endothelial function.