Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision

Abstract

Angiogenesis is critical during development, wound repair, and cancer progression. During angiogenesis, some endothelial cells adopt a tip phenotype to lead the formation of new branching vessels; the trailing stalk cells proliferate to develop the vessel. Notch and VEGF signaling mediate the selection of these tip endothelial cells. However, how Jagged, a Notch ligand that is overexpressed in cancer, affects angiogenesis remains elusive. Here, by developing a theoretical framework for Notch-Delta-Jagged-VEGF signaling, we found that higher production levels of Jagged destabilizes the tip and stalk cell fates and can give rise to a hybrid tip/stalk phenotype that leads to poorly perfused and chaotic angiogenesis, which is a hallmark of cancer. Consistently, the signaling interactions that restrict Notch-Jagged signaling, such as Fringe, cis-inhibition, and increased production of Delta, stabilize tip and stalk fates and limit the existence of hybrid tip/stalk phenotype. Our results underline how overexpression of Jagged can transform physiological angiogenesis into pathological one.

Different angiogenic potentials of mesenchymal stem cells derived from umbilical artery, umbilical vein and wharton’s jelly

“…Furthermore, Jagged1 expression was the highest in UCA-PSCs, followed by UCV-PSCs, and then WJ-MSCs ( Figure 6(b)). Jagged1 is well-known to play an important role in both physiological and pathological angiogenesis [23]. The Jagged1 mRNA levels were measured by qRT-PCR, and the results were in line with those of the microarray analysis ( Figure 6(c)).…”

Time to Decide? Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis

“…Therefore, the system exhibits interesting multi-stable dynamics. Presence of bistability in notch-DLL signaling with respect to EC patterning has recently been shown by us [32], and others [24], [17]. Recently EC patterning has been shown to exhibit diseased ‘hybrid states’ [17] that result due to overexpression of Jagged-1, (another Notch ligand).…”

“…Importantly, the model predicts the presence of partial states apart from the known Tip and Stalk states of the system. An abnormal “hybrid” state has previously been reported in a model of jagged-notch signaling [17] but was linked only to a diseased condition. Here, by considering specific cellular umwelts and internal regulation occurring in normally sprouting vessels we predict partial states are intrinsic to the normal unfolding of the process, in particular playing a role during cell rearrangement.…”

“…This is because higher V.R2 activation stimulates actin polymerization, filopodia and cell migration [15,16]. Most modeling studies involving EC patterning and notch-DLL signaling to date [10,17] have not focused on the specific timing of the process during angiogenic sprouting, or how different local environments of a cell in a sprout would impact this speed. Here we explicitly study and predict the effects of asynchrony in EC patterning at different regions of a sprout as well as the impact of internal regulators of Notch-DLL signaling.…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…Much evidence, however, supports that DLL4's control on vascular sprouting is via its downstream factors, Hey1/2. It is acknowledged that epithelium with higher VEGFR2 emerges at the tip position and sustained VEGFR2 pathway activation results in excessive sprouting (57)(58)(59). Strikingly, Hey1, as well as Hey2, can suppress VEGFR2 expression and eliminate the increased frequency of epithelial cells at the tip position (58,60,61).…”