*5.1.3 Occludin and pulmonary vascular injury diseases*

Pulmonary vascular endothelial cells form a complete cell barrier, participate in the regulation of vascular homeostasis, and maintain the normal operation of the body. Under pathological conditions (diabetes, hypertension, and hyperlipidemia), the pulmonary vascular endothelial barrier is damaged, resulting in vascular endothelial dysfunction and chronic structural damage. Tight junction proteins play an important role in maintaining the integrity of the pulmonary vascular endothelial barrier. As an important component of TJ, occludin has been shown to be down-regulated in a variety of pulmonary vascular injury-related diseases. (1) Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary endothelial cell dysfunction and vascular remodeling. Histological evaluation of mouse model of pulmonary arterial hypertension shows downregulation of occludin expression in pulmonary vessels [87]; (2) the expression of occludin in pulmonary artery endothelial

cells of diabetic and hypertensive model mice was reduced, and nitric oxide (NO), superoxide dismutase, and inducible NO synthase were severely imbalanced, suggesting that occludin may be involved in the production of vascular endothelial NO [88]; (3) studies have found that the occludin protein in the pulmonary artery endothelial cells of the rat model of acute lung injury is lost, the endothelial permeability is increased, the vascular inflammatory response is increased, and oxidative stress and other pathological states occur [89]. In conclusion, abnormal expression and distribution of occludin are closely related to pulmonary vascular lesions.

## *5.1.4 Occludin and renal vascular injury diseases*

Kidney is one of the organs with the most abundant distribution of endothelial cells. Under physiological conditions, renal endothelium can mediate signal communication between various parts of the kidney, stabilize renal osmotic pressure, and regulate vascular permeability. Under pathological conditions such as ischemia, inflammation, and sepsis, renal vascular endothelial permeability is increased, renal metabolism is impaired, and the basal layer of endothelial cells is thickened, which induces endothelial damage and leads to plasma leakage. Occludin is involved in maintaining the barrier function of renal endothelial cells, and a large number of basic studies on occludin and renal vascular injury have found that (1) The abnormal expression and distribution of occludin in renal endothelial cells, the imbalance of electrolytes such as sodium, potassium, and chloride, and the deterioration of renal injury exist in the rat model of renal ischemia-reperfusion, suggesting that the abnormal expression and distribution of occludin in renal vascular endothelial cells affect renal function homeostasis [90]; (2) High glucose and high fat stimulate human glomerular endothelial cells, decrease the expression of occludin, and damage renal endothelial barrier function, which leads to development of diabetic nephropathy [91]; (3) renal dysfunction caused by hyperoxia is closely related to renal endothelial tight junction protein occludin [92]. In conclusion, the decreased expression of occludin in renal endothelial cells under pathological conditions may be a new marker of renal vascular injury.

## *5.1.5 Occludin and other arterial diseases*

The blood retinal endothelial barrier maintains the integrity of retinal tissue. The level of occludin in endothelial cells can dynamically regulate the intracellular signal transduction system, promote the transport of nutrients, and limit the transport of harmful substances, which is extremely important for maintaining the blood retinal endothelial barrier. Studies have found that: (1) The phosphorylation of occludin S490 in retinal endothelial cells regulates the proliferation and angiogenesis of retinal endothelial cells [6]; (2) the decreased expression of occludin in endothelial cells of diabetic retinopathy can induce inflammatory cell infiltration, suggesting that the loss of occludin at the blood-retinal barrier leads to increased endothelial cell permeability, which is an important factor for mediating the aggravation of vascular inflammatory responses [93]; (3) when neonatal rats exposed to hypoxia, the expression of occludin in retinal endothelial cells decreased, vacuoles appeared in endothelial cytoplasm, and mitochondrial vacuoles and multivesicles accumulated in capillary lumen, suggesting that occludin was involved in the occurrence of hypoxic stress response [94]; (4) relevant studies have shown that exogenous stimuli (high sugar, long-term high-fat diet, long-term smoking) can inhibit the expression of occludin in the vascular endothelium, resulting in an increase in vascular permeability, which

in turn causes the occurrence of oxidative stress in vascular endothelial cells [89]. According to the above research results, it is suggested that the maintenance of blood retinal endothelial barrier integrity is closely related to occludin.

## **5.2 Occludin and venous vascular diseases**

Venous vessels maintain venous barrier function by expressing abundant occludin. Recent studies on occludin in venous endothelial cells have shown that: (1) Serum occludin levels are higher in patients with jugular vein stenosis [95]; (2) Nitta et al. found that in mouse model of retinal vein occlusion, venous vascular inflammation increased, occludin expression decreased, and retinal edema occurred; conversely, inhibiting vascular inflammation could alleviate the decrease in occludin expression and maintain retinal homeostasis [96]; (3) studies on mice with ischemic stroke found that early cerebral venous filling and dilation were associated with occludin displacement and abnormal expression and distribution [97]. In conclusion, the maintenance of the venous homeostasis is inseparable from the regulation of occludin.
