De novo synthesis of cytoskeleton-regulatory proteins triggered by the MKL (megakaryoblastic leukemia)/SRF (serum response factor) transcriptional system in response to pro-angiogenic growth factors lies at the heart of endothelial cell (EC) migration (a critical element of angiogenesis) and neovascularization. This study explores whether pharmacological intervention of MKL/SRF signaling axis by CCG-1423 is able to suppress angiogenesis. Our studies show that CCG-1423 inhibits migration and cord morphogenesis of EC in vitro and sprouting angiogenesis ex vivo and in vivo, suggesting CCG-1423 could be a novel anti-angiogenic agent. Kymography analyses of membrane dynamics of EC revealed that CCG-1423 treatment causes a major defect in membrane protrusion. CCG-1423 treatment led to attenuated expression of several actin-binding proteins that are important for driving membrane protrusion including ArpC2, VASP and profilin1 (Pfn1) with the most drastic effect seen on the expression of Pfn1. Finally, depletion of Pfn1 alone is also sufficient for a dramatic decrease in sprouting angiogenesis of EC in vitro and ex vivo, further suggesting that Pfn1 depletion may be one of the mechanisms of the anti-angiogenic action of CCG-1423.
Physical forces are important participants in the cellular dynamics that shape developing organs. During heart formation, for example, contractility and blood flow generate biomechanical cues that influence patterns of cell behavior. Here, we address the interplay between function and form during the assembly of the cardiac outflow tract (OFT), a crucial connection between the heart and vasculature that develops while circulation is underway. In zebrafish, we find that the OFT expands via accrual of both endocardial and myocardial cells. However, when cardiac function is disrupted, OFT endocardial growth ceases, accompanied by reduced proliferation and reduced addition of cells from adjacent vessels. The flow-responsive TGFβ receptor Acvrl1 is required for addition of endocardial cells, but not for their proliferation, indicating distinct modes of function-dependent regulation for each of these essential cell behaviors. Together, our results indicate that cardiac function modulates OFT morphogenesis by triggering endocardial cell accumulation that induces OFT lumen expansion and shapes OFT dimensions; moreover, these morphogenetic mechanisms provide new perspectives regarding the potential causes of cardiac birth defects.
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
In children with single ventricle physiology, the Glenn procedure is performed to redirect venous return from the superior vena cava directly to the pulmonary arteries and route venous return from the inferior vena cava exclusively to the systemic circulation. Although this surgery successfully palliates the hemodynamic stress experienced by the single ventricle, patients frequently develop pulmonary arteriovenous malformations (PAVMs). Interestingly, PAVMs may regress upon rerouting of hepatic venous effluent to the pulmonary vasculature, suggesting the presence of a circulating "hepatic factor" that is required to prevent PAVMs. Here, we test the hypothesis that hepatic factor is bone morphogenetic protein 9 (BMP9) and/or BMP10. These circulating ligands are produced by the liver and activate endothelial endoglin (ENG)/ALK1 signaling, and mutations in ENG and ALK1 cause hereditary hemorrhagic telangiectasia, a genetic disease associated with AVM development. However, we found no within-subject variation in BMP9, BMP10, or BMP9/10 plasma concentrations when sampled from five cardiovascular sites, failing to support the idea that the Glenn would limit access of these ligands to the lung vasculature. Unexpectedly, however, we found a significant decrease in all three ligand concentrations in Glenn cases versus controls. Our findings suggest that BMP9/BMP10/ENG/ALK1 signaling may be decreased in the Glenn vasculature but fail to implicate these ligands as hepatic factor.
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