Properdistatin inhibits angiogenesis and improves vascular function in human melanoma xenografts with low thrombospondin-1 expression

Abstract

In this study, the effect of properdistatin, a novel peptide derived from the thrombospondin 1 (TSP-1) domain of properdin, was investigated in three melanoma xenograft models with different TSP-1 expression. The tumors were grown in dorsal window chambers and were treated with 80 mg/kg/day properdistatin or vehicle. Morphological parameters of the tumor vasculature were assessed from high resolution transillumination images. Blood supply time (i.e., the time required for arterial blood to flow from a supplying artery to downstream microvessels) and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Gene and protein expression of TSP-1 were assessed with quantitative PCR and immunohistochemistry, respectively. Properdistatin treatment inhibited angiogenesis in low TSP-1 expressing tumors but did not alter the vasculature in high TSP-1 expressing tumors. In low TSP-1 expressing tumors, properdistatin selectively removed small-diameter capillaries, but did not change the morphology of tumor arterioles or tumor venules. Properdistatin also reduced blood supply times and increased plasma velocities, implying that the treatment reduced the geometric resistance to blood flow and improved vascular function.

Potential role of sirtuin 1 in Müller glial cells in mice choroidal neovascularization

“…In the present study, we first demonstrated that RSV-activated MGCs showed increased expression of the antiangiogenic factors, PEDF and TSP-1, as well as the phagocytic ability. PEDF is well known to reduce migration and promote apoptosis of endothelial cells [ 21 ], and TSP-1 induces apoptosis of endothelial cells and prevents them from responding to a wide variety of angiogenic stimulators [ 22 ]. While MCGs are known to express PEDF and TSP-1 under normal conditions [ 6 ], we demonstrated that RSV treatment upregulated PEDF and TSP-1 expression, and may have anti-CNV properties.…”

The thrombospondin module 1 domain of the matricellular protein CCN3 shows an atypical disulfide pattern and incomplete CWR layers

“…However, the functional implication of this structural division of disulfide connectivity is as yet unclear, even though Tan et al (2002) originally suggested that the division of the top disulfide also divides the effect on angiogenesis. It still appears to be true that several proteins from the Cys 1 -Cys 4 disulfide group, including CCN proteins, spondins and HB-GAM, simulate angiogenesis (Kazanskaya et al, 2008;Papadimitriou et al, 2016;Kubota & Takigawa, 2007), while the Cys 3 -Cys 4 group, including thrombospondins, Unc5, properdins, ADAMTS proteins and papillin, inhibit angiogenesis (Lawler & Lawler, 2012;Larrivé e et al, 2007;Gaustad et al, 2016;Sun et al, 2015;Karagiannis & Popel, 2007). However, knowledge of more proteins with known functions from each group, and ideally complex structures with ligands bound differently owing to the different top disulfide, are needed before we can make a reliable statement regarding the correlation, if any, between the disulfide group and the functionality.…”

Integration of pro- and anti-angiogenic signals by endothelial cells

“…This function is mainly meditated through the TSRs, which bind to the CLESH domain of CD36 and to β1 integrins. The importance of the anti-angiogenic activity of the TSRs is underscored by the fact that other proteins that contain TSRs also have anti-angiogenic activity (Gaustad et al 2016). Engagement of α5β1 integrin by 3TSR inhibits endothelial cell migration in a PI3K-dependent manner (Short et al 2005) (Fig.…”