Pulmonary Endothelial Cell Migration Research Articles

DYZY01 alleviates pulmonary hypertension via inhibiting endothelial cell pyroptosis and rescuing endothelial dysfunction

Pulmonary hypertension (PH) is a malignant pulmonary vascular disease with a poor prognosis. Although the development of targeted drugs for this disease has made some breakthroughs in recent decades, PH remains incurable. Therefore, innovative clinical treatment methods and drugs for PH are still urgently needed. DYZY01 is a new drug whose main ingredient is high-purity cannabidiol, a non-psychoactive constituent of cannabinoids that was demonstrated to have anti-inflammatory and anti-pyroptosis properties. Several recent studies have found cannabidiol could improve experimental PH, whereas the mechanistic effect of it warrants further investigation. Thus, this study aimed to investigate whether DYZY01 can treat PH by inhibiting inflammation and pyroptosis and to reveal its underlying mechanism. We established hypoxia and monocrotaline (MCT)-induced PH rat models in vivo and treated them with either DYZY01 (10,50 mg/kg/d) or Riociguat (10 mg/kg/d) by oral administration. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and extent of vascular remodeling were measured. Meanwhile, the effect of DYZY01 on human pulmonary arterial endothelial cells (HPAECs) was assessed in vitro. The results indicated that DYZY01 significantly reduced mPAP and RVHI in PH rats and reversed the extent of pulmonary vascular remodeling. This improvement may have been achieved by reducing endothelial cell pyroptosis via inhibiting the NF-κB/NLRP3/Caspase-1 pathway. Furthermore, DYZY01 could improve endothelial vascular function, possibly by regulating the secretion of vasodilator factors and inhibiting the proliferation and migration of pulmonary endothelial cells.

Functional Impact of Human Genetic Variants of COL18A1/Endostatin on Pulmonary Endothelium.

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small-vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood, but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. ES (endostatin), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan COL18A1 (collagen α1[XVIII] chain). Elevated serum ES is associated with increased mortality and disease severity in PAH. A nonsynonymous variant of ES (aspartic acid-to-asparagine substitution at amino acid 104; p.D104N) is associated with differences in PAH survival. Although COL18A1/ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. In the present study, we characterized the effects of exogenous ES on human PEC biology and signaling. We demonstrated that ES inhibits PEC migration, proliferation, and cell survival, with significant differences between human variants, indicating that they are functional genetic variants. ES promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of TSP-1 (thrombospondin 1). ES inhibits PEC migration via an ID1/TSP-1/CD36-dependent pathway, in contrast to proliferation and apoptosis, which require both CD36 and CD47. Collectively, the data implicate ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes in PAH.

Found in Inflammatory Zone 1 Induces Angiogenesis in Murine Models of Asthma

Angiogenesis plays an important role in airway remodeling that occurs in asthma, while the mechanisms underlying this process are not fully elucidated. Found in inflammatory zone 1 (FIZZ1), a novel cysteine-rich secreted protein, is able to promote proliferation and migration of pulmonary endothelial cells, and to upregulate the expression of vascular endothelial growth factor (VEGF). However, the role of FIZZ1 in angiogenesis of asthma has not been fully investigated. Murine models of asthma were sensitized on days 1 and 14 by ovalbumin (OVA) and challenged with 2% OVA beginning from day 21. Mice were divided into four groups: asthmatic mice challenged with OVA for 7 days, 14 days, and 28 days, respectively, and healthy control mice that were sensititized and challenged with PBS. The expressions of FIZZ1, VEGF, and von Willebrand factor (vWF)-stained vascular area were measured in asthmatic mice and healthy controls (n = 10). Histologic examination was also performed on airway inflammation. Levels of FIZZ1 were increased significantly after allergic challenge, reached the peak by 7 days, declined by 14 days, and were reduced further by 28 days after OVA challenge. Similarly, percentages of vWF-stained vascular area (percentage of vascularity) were largely increased within 7 days and then reduced from day 14 of challenge. The expression of FIZZ1 in asthma was positively correlated with vWF-stained vascular area and VEGF expression in a time-dependent manner. FIZZ1 expression was significantly correlated with the percentage of vascularity and VEGF expression, suggesting that FIZZ1 and VEGF have crucial roles in angiogenesis of asthma.