Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

Abstract

Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/β-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.

Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: New targets for the treatment of portal hypertension?

“…Furthermore, there is some evidence that an inhibition of angiogenesis can even worsen fibrosis [27][28][29]. For example, in a recent study performed in two complementary models of cirrhosis, the administration of Cilengitide, an inhibitor of the vitronectin receptor integrin abv3 that plays an important role in liver angiogenesis, promoted hepatic fibrosis and inflammation despite its anti- angiogenic effects [30].…”

“…Furthermore, the beneficial role of angiogenesis in tissue regeneration and repair should not be underestimated. Lastly, as discussed earlier, some anti-angiogenic interventions provide evidence for the detrimental effects in preclinical models [27][28][29][30].…”

Evolving therapies for liver fibrosis

“…However, antifibrotic effects were evident with polykinase inhibitors such as sunitinib and sorafenib that, apart from angiogenic VEGF or FGF receptors on LSECs, also target numerous other cells and kinases involved in proliferation, ECM turnover, and immune regulation (67,68). This lack of specificity may explain the finding that treatment with anti-VEGF antibody and an antagonist to integrin αvβ3, therapies that inhibit LSEC proliferation (but also affect the proliferation of endothelia of larger vessels) may worsen advanced biliary, perisinusoidal, and interstitial kidney fibrosis (69)(70)(71). Moreover, specific inhibition of VEGF mitigates biliary fibrosis progression but retards fibrosis reversal after jejunoileal anastomosis (72).…”

Vascular Endothelial Growth Factor in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…Furthermore, the underlying pathogenesis of fibrosis in ARDS may differ compared to other diseases/disease models and thus it is difficult to draw conclusions about ALI/ADRS from these studies. Research is required to explore this area in more detail [129,130]. …”