Abstract
Late endothelial progenitor cells (LEPCs) are derived from mononuclear cells (MNCs) and are thought to directly incorporate into blood vessels and differentiate into mature endothelial cells (ECs). Using transcriptome and proteome analysis, we identified distinctive LEPC profiles and found that Hedgehog-interacting protein (HIP) is strongly expressed in LEPCs. Inhibition of HIP by lentiviral knockdown activated canonical hedgehog signaling in LEPCs, while it activated non-canonical hedgehog signaling in ECs. In LEPCs, HIP knockdown induced much enhanced tube formation and resistance to apoptosis under oxidative stress conditions via canonical hedgehog signaling. Although HIP is strongly expressed in proliferating LEPCs, HIP expression is down-regulated during angiogenesis and under oxidative stress condition. Moreover, when LEPCs are treated with angiogenic triggers such as VEGF and FGF2, HIP expression is reduced. Our findings suggest that HIP blocks LEPC angiogenesis and regulate survival when there is no angiogenic stimulation. HIP inhibition in LEPCs enhanced tube formation and reduced apoptosis, resulting in improved angiogenesis.
Highlights
EPCs are a heterogeneous population of which two subtypes have been identified – earlyEPCs and lateEPCs (LEPCs)
Among the 101 genes enriched in the endothelial lineage compared to mononuclear cells (MNCs), we focused on Hedgehog-Interacting Protein (HIP) because of the importance of Hh signaling during developmental angiogenesis
Western blot results confirmed that Gli-1 expression was enhanced upon sonic hedgehog (Shh) treatment in Late endothelial progenitor cells (LEPCs), while Shh treatment yielded no change in Human umbilical vein endothelial cells (HUVECs) (Fig. 5K). These results suggest that LEPCs and endothelial cells (ECs) respond differently to Hh ligands and that canonical Hh signaling plays an important role in LEPCs
Summary
EPCs are a heterogeneous population of which two subtypes have been identified – earlyEPCs (eEPCs) and lateEPCs (LEPCs). EEPCs do not differentiate into mature endothelial cells (EC) and promote angiogenesis indirectly via paracrine mechanisms[6,7]. Based on these physiological differences, only LEPCs are thought to give rise to mature endothelial cells following their differentiation from mononuclear cells (MNCs). Hh ligands augment bone marrow-derived eEPC proliferation, migration and VEGF production via Gli-1 dependent canonical Hh signaling[12,13]. In this study, using high-throughput RNA sequencing and mass spectrometry-based proteome analysis, we present a comprehensive approach for the characterization of endothelial lineage cells. HIP is highly expressed in endothelial cells but down-regulated during angiogenesis and in several types of tumors[17]. We hypothesized that HIP plays an important role in the tight regulation of LEPC functions
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