Role of Vascular Endothelial Growth Factor Signaling in Schistosoma‐Induced Experimental Pulmonary Hypertension

Abstract

There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model.

Bevacizumab as a potential anti‐angiogenic therapy in schistosomiasis: A double‐edged, but adjustable weapon

“…It almost has 10 times higher affinity to VEGF than VEGF‐R2. Many immunohistochemical studies reported a significant correlation between VEGF‐R1 expression and VEGF level 14,39 …”

“…Furcocercous cercariae were collected from laboratory‐bred S mansoni ‐infected Biomphalaria alexandrina snails purchased from Theodor Bilharz Research Institute, Schistosoma unit. Infection was done by immersing mouse tail into a vial containing a suspension of living cercariae for 30 minutes (100 cercariae per mouse) 14 . Infection was confirmed by regular coproscopy starting from the 4 th week pi to detect the characteristic S mansoni eggs.…”

“…VEGF‐A is the most characterized member in the VEGF family and acts through VEGF‐R‐1 and VEGF‐R‐2 activation 11‐13 9,10 . According to Chabon et al ( 2014 ), VEGF‐A over expression becomes evident in certain types of tissue injury, and is responsible for the vascular overgrowth and remodelling in schistosomiasis 14 …”

Schistosomiasis-associated pulmonary arterial hypertension: a systematic review

“…A total of 18 studies examining the pathophysiological mechanisms of Sch-PAH were eligible for inclusion (table E2) [3,25,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Mechanisms involved in the pathogenesis of iPAH were selected from the proceedings of the 6th World Symposium on Pulmonary Hypertension and compared to pathophysiologic pathways in Sch-PAH (table 1 and figure 2) [74].…”

Hypoxic pulmonary hypertension and the role of extra-cellular hemoglobin in perivascular macrophage accumulation

“…In our model this likely contributes to an exacerbation of pulmonary vascular remodeling and worsening PH associated with hypoxia plus extracellular Hb. Several groups have evaluated the role of inflammation on the initiation and progression of PH in hypoxia, scleroderma, parasitic infections and anemia [18][19][20][21] . Stenmark et al have demonstrated compelling results to suggest that fibroblasts and immunomodulatory cells including macrophages and other cell types contribute to the expansion of the pulmonary vascular vaso vasorum during hypoxia.…”