How Do I Prevent Endothelial Dysfunction?

Vascular endothelial cells are a layer of monocytes between the blood stream and the tissues of the blood vessel wall. They can secrete a series of vasoactive substances such as NO, PGI2, and ET-1 through three ways: autocrine, endocrine, and paracrine. Tonicity, antithrombotic, inhibit smooth muscle cell proliferation and vascular wall inflammation. NO is the most important vasodilator produced by endothelial cells. NO synthase (eNOs) of endothelial cells act on L-arginine. NO can diffuse to vascular wall smooth muscle cells to activate ornithine cyclase and mediate cGMP. Regulated Vasodilation. Not only that, NO also inhibits platelet aggregation, inhibits monocytes from adhering to endothelial cells, and inhibits smooth muscle cell proliferation. However, when the vascular endothelium is affected by a series of harmful factors, the vasodilators released by endothelial cells are reduced, the vasoconstrictor factors are increased, the vascular homeostasis is broken, and eventually a series of cardiovascular events occur.

Endothelial injury

Overview of endothelial injury

Vascular endothelial cells are a layer of monocytes between the blood stream and the tissues of the blood vessel wall. They can secrete a series of vasoactive substances such as NO, PGI2, and ET-1 through autocrine, endocrine, and paracrine pathways to regulate blood vessels. Tonicity, antithrombotic, inhibit smooth muscle cell proliferation and vascular wall inflammation. NO is the most important vasodilator produced by endothelial cells. NO synthase (eNOs) of endothelial cells act on L-arginine. NO can diffuse to vascular wall smooth muscle cells to activate ornithine cyclase and mediate cGMP. Regulated Vasodilation. Not only that, NO also inhibits platelet aggregation, inhibits monocytes from adhering to endothelial cells, and inhibits smooth muscle cell proliferation. However, when the vascular endothelium is affected by a series of harmful factors, the vasodilators released by endothelial cells are reduced, the vasoconstrictor factors are increased, the vascular homeostasis is broken, and eventually a series of cardiovascular events occur.

Vascular Endothelial Damage to Cardiovascular Disease

Changes in the structure and function of endothelial cells are the common pathological basis of various cardiovascular diseases. It has been confirmed that the endothelium structure and function of patients with hypertension, coronary heart disease and other serious damage.

Endothelial injury and hypertension

Almost all patients with essential hypertension have vascular endothelial damage. Although the cause and effect of endothelial damage and hypertension have not yet been determined, the current research results tend to believe that endothelial damage in hypertension patients is secondary to hypertension. A sharp rise in blood pressure damages endothelial cells, reduces the release of NO by endothelial cells, and reduces the bioavailability of NO. The mechanism may be that the vascular endothelium is damaged, which reduces the action substrate of eNOS, L-arginine. Endothelial dysfunction in hypertensive patients may also be genetically related. Zizek and other studies have shown that compared with normotensive persons without a family history of hypertension, normotensive persons with a family history of hypertension have significantly higher left ventricular cardiac index.

Endothelial injury and coronary heart disease

Coronary heart disease is one of the common diseases of cardiovascular disease, and its pathological basis is that lipids gather under the damaged endothelium to form atherosclerotic plaques. Low-density lipoprotein (LDL) can damage the L-arginine / NO pathway in a variety of ways. The RAS system plays an important role in vascular endothelial damage. Angiotensin receptor type I (At1R) and active oxide release are increased. , Vascular cell apoptosis, increased expression of oxidized low-density lipoprotein receptors, increased adhesion molecules and pro-inflammatory factors, and high cholesterol can increase At1R density and At1R response to vasoconstrictive substances. At1R can also increase the production of angiotensinogen and angiotensin and damage the vascular endothelium. At1R antagonists significantly improve high cholesterol-related endothelial dysfunction. Another mechanism may be related to the production of dimethylarginine (ADMA), an endogenous competitive inhibitor of NO synthase. Oxidized low-density lipoprotein (ox-LDL) in the vessel wall inhibits dimethylarginine dimethyl Aminohydrolase (DDAH) reduces ADMA degradation. In addition, ADMA can also increase the expression of ox-LDL receptor LOX-1.

Vascular endothelial injury

Vascular endothelium is affected by many factors, especially oxidative stress, renin-angiotensin system, oxidized low density lipoprotein, homocysteine and so on.

Endothelial injury and oxidative stress

The imbalance between the generation and removal of oxygen free radicals produces an "oxidative stress" response. Under physiological conditions, oxidative stress can regulate cell function, receptor signaling and immune response, but excessive oxidative stress can promote the growth and migration of vascular smooth muscle and inflammatory cells, degrade the extracellular matrix, promote endothelial cell apoptosis, Activation of transcription factors (NF-kB, AP-1), promotion of inflammatory factors and overexpression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and other methods damage endothelial cells. Oxidative stress is mainly mediated by oxygen free radicals, collectively referred to as reactive oxygen species (ROS). ROS is mainly related to NADPH-oxidase activated by angiotensin II (AtII), blood flow shear stress, and hyperglycemia. ROS increases the concentration of calcium in the cytoplasm, reduces the production of NO, and weakens the vasodilation effect. At the same time, calcium influx consumes ATP, which reduces ATP. The combined reduction of NO and ATP causes damage to the vascular endothelium.

- Vascular Endothelial Injury Renin-Angiotensin System and Vascular Endothelial Damage

The renin-angiotensin system (RAS) plays an important role in the occurrence and development of cardiovascular disease. Renin can convert angiotensinogen to angiotensin I (AtI). AtI is an angiotensin-converting enzyme (ACE) and Other enzymes produce angiotensin II (AtII), which has a strong vasoconstrictive effect. AtI not only increases vascular resistance, but also stimulates the proliferation of vascular smooth muscle and cardiomyocytes, promotes the occurrence of oxidative stress and promotes thrombosis. ACE promotes the production of AtII, inhibits the activity of bradykinin, and reduces the release of NO.

Vascular endothelial injury oxidized low density lipoprotein and vascular endothelial injury

Low density lipoprotein (LDL) accumulates and oxidizes in the blood vessel wall to form oxidized low density lipoprotein (ox-LDL). ox-LDL up-regulates gene expression of various adhesion molecules such as MCP-1, ICAM-1, VCAM-1, P-selectin, and E-selectin, and promotes monocytes to adhere to vascular endothelial cells. These effects of ox-LDL are mainly achieved by activating its receptor LOX-1. Endothelial cells cause activation, dysfunction, loss of integrity and secretory dysfunction of endothelial cells through LOX-uptake of ox-LDL. ox-LDL combined with LOX-1 can also promote endothelial cell apoptosis.

Endothelial microparticles and vascular endothelial injury

Endothelial microparticles are tiny vesicles with a diameter of 0.2 m to 1 m released from the cell membrane when endothelial cells are stimulated, damaged, or undergo endothelial cell apoptosis, and carry certain antigenic characteristics of endothelial cells. Studies have shown that EMP released by endothelial cells can reduce the activity of endothelial cell NO synthase (eNOs), reduce the NO synthesis with vasodilating effect, reduce the bioavailability of NO, and destroy the NO-mediated endothelium-dependent vasodilation function. In addition, EMP is also associated with an increase in reactive oxygen species (ROS) that disrupt endothelial cell function.

Endothelial injury homocysteine and endothelial injury

Homocysteine is an excitatory neurotransmitter. High concentrations of homocysteine increase superoxide production, while the intracellular antioxidant enzyme glutathione peroxidase or extracellular superoxide dismutase It is inhibited by high concentrations of homocysteine to reduce the inactivation of superoxide, both of which lead to a sharp increase in superoxide, cause the occurrence of oxidative stress reactions, and eventually damage the blood vessel endothelium. In addition, the use of folic acid can partially alleviate the impairment of endothelial function caused by homocysteine. Therefore, homocysteine is one of the factors that cannot be ignored in vascular endothelial injury.

Repair of vascular endothelium

Endothelial cell damage leads to an imbalance of released vasodilator and vasoconstrictor factors, of which NO and angiotensin II are the most important. However, endothelial cell injury is a reversible change. Endothelial injury can be repaired through exercise, calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, traditional Chinese medicine and lifestyle interventions.

ACEI

ACE inhibitors (ACEI) protect endothelial cells mainly through two pathways: one is to inhibit ACE and reduce the production of AtII to protect endothelial cells from stress damage; the other is to inhibit the degradation of bradykinin, so that endothelial cells release more NO . These two mechanisms have been confirmed in animal experiments and in vitro experiments.

ARB

Recent studies have shown that AtII stimulates the accumulation of peroxides, hydroxides, and peroxynitrites by stimulating NADPH oxidase, leading to the occurrence of inflammatory reactions. Although the mechanism by which ARBs are beneficial for endothelial function repair is not completely clear, studies have shown that ARBs can exert antioxidant effects by inhibiting the activity of NADPH produced by AtII stimulation, reducing the production of superoxide and NO degradation. In addition, ARBs can also enhance the antioxidant capacity of superoxide dismutase and enhance the activity of NO.

beta blockers

Beta-blockers are the first-line drugs for treating hypertension. However, the clinical role of traditional beta-blockers has been questioned. The third-generation beta-blockers (carvedilol, labello, etc.) And Nebivolol) have been used clinically. The common feature of these new drugs is the relaxation of peripheral blood vessels, but the mechanisms are different. Carvedilol is an alpha-1 adrenergic blocker. Studies have shown that in patients with hypertension and type 2 diabetes, carvedilol can increase blood flow-mediated vasodilation and improve endothelial function without affecting lipids. Or sugar metabolism. Nebivolol is a highly selective 1 adrenergic blocker, which can stimulate the release of NO by endothelial NO synthase (eNOs), increase blood flow-mediated vasodilation, reduce peripheral vascular resistance and anti-oxidative stress. . Nebivolol also has the effects of increasing insulin sensitivity and regulating lipid metabolism.

Phosphodiesterase-5 inhibitor

Phosphodiesterases (PDEs) are a class of proteins that regulate the level of intracellular cyclic nucleotides (such as cyclic guanosine monophosphate cGMP and cyclic adenosine monophosphate cAMP). Phosphodiesterase-5 (PDE5) inhibitors can increase cGMP activity, enhance the NO signaling pathway, and produce a vasodilation effect.

HMG CoA reductase inhibitor

Statins not only reduce the occurrence of cardiovascular events, but also reduce total mortality, and can be used as primary and secondary preventive medication for cardiovascular events. Statins directly activate eNOs to promote the rapid release of NO by endothelial cells and inhibit endothelin-1 from exerting antioxidant effects, thereby achieving endothelial protection. The mechanism may be related to the reduction of triglyceride, low density lipoprotein (LDL) levels, direct reduction of ET-1 secretion, reduction of ox-LD levels, increased release of NO synthesis, and stimulation of increased synthesis of ET-1 receptors on cell membranes. Statins can also reduce At1R expression and down-regulate its function.

^[1] Traditional Chinese Medicine and Lifestyle Intervention

Traditional Chinese medicine hospitals have also made many research results in improving vascular endothelial function and treating cardiovascular diseases. Our laboratory research confirmed that berberine can inhibit the production of endothelial microparticles and enhance the function of endothelial progenitor cells. In addition, Naoxintong, Tongxinluo, and Xuezhikang capsules have good effects on repairing vascular endothelium.

The destruction of vascular endothelial homeostasis is closely related to the living environment and lifestyle. Obesity, smoking, bad living habits, and chronic stress can cause damage to the vascular endothelium. Therefore, a good living environment and lifestyle are of great significance for the maintenance of vascular endothelium. ACC / AHA recommends at least 30 minutes of aerobic exercise every day to reduce cardiovascular events. Regardless of the presence of cardiovascular risk factors or cardiovascular disease, regular aerobic exercise can significantly increase the bioavailability of NO and improve vascular endothelial function. Regular aerobic exercise can also reduce the oxidative stress response of blood vessels. Short-term and long-term follow-up studies have confirmed that regular aerobic exercise can reduce CRP, fibrinogen, ICAM-1, VCAM-1, P-selectin and MMP-9 and other pro-inflammatory factors. Other lifestyle interventions include smoking cessation, weight loss, and diet control.