The role of angiogenesis in the growth of organs and tumors is widely recognized. Vascular–organ interaction is a key mechanism and a concept that enables an understanding of all biological phenomena and normal physiology that is essential for human survival under pathological conditions. Recently, vascular endothelial cells have been classified as a type of innate immune cells that are dependent on the pathological situations. Moreover, inflammatory cytokines and signaling regulators activated upon exposure to infection or various stresses play crucial roles in the pathological function of parenchymal cells, peripheral immune cells, stromal cells, and cancer cells in tissues. Therefore, vascular–organ interactions as a vascular microenvironment or tissue microenvironment under physiological and pathological conditions are gaining popularity as an interesting research topic. Here, we review vascular contribution as a major factor in microenvironment homeostasis in the pathogenesis of normal as well as cancerous tissues. Furthermore, we suggest that the normalization strategy of pathological angiogenesis could be a promising therapeutic target for various diseases, including cancer.

Recent studies have revealed that microRNAs (miRs) play important roles in the regulation of angiogenesis. In this study, we have characterized miR-382 upregulation by hypoxia and the functional relevance of miR-382 in tumor angiogenesis. miRs induced by hypoxia in MKN1 human gastric cancer cells were investigated using miRNA microarrays. We selected miR-382 and found that the expression of miR-382 was regulated by HIF-1α. Conditioned media (CM) from MKN1 cells transfected with a miR-382 inhibitor (antagomiR-382) under hypoxic conditions significantly decreased vascular endothelial cell (EC) proliferation, migration and tube formation. Algorithmic programs (Target Scan, miRanda and cbio) predicted that phosphatase and tensin homolog (PTEN) is a target gene of miR-382. Deletion of miR382-binding sequences in the PTEN mRNA 3'-untranslated region (UTR) diminished the luciferase reporter activity. Subsequent study showed that the overexpression of miR-382 or antagomiR-382 down- or upregulated PTEN and its downstream target AKT/mTOR signaling pathway, indicating that PTEN is a functional target gene of miR-382. In addition, PTEN inhibited miR-382-induced in vitro and in vivo angiogenesis as well as VEGF secretion, and the inhibition of miR-382 expression reduced xenograft tumor growth and microvessel density in tumors. Taken together, these results suggest that miR-382 induced by hypoxia promotes angiogenesis and acts as an angiogenic oncogene by repressing PTEN.

Cancer creates a complex tumor microenvironment (TME) composed of immune cells, stromal cells, blood vessels, and various other cellular and extracellular elements. It is essential for the development of anti-cancer combination therapies to understand and overcome this high heterogeneity and complexity as well as the dynamic interactions between them within the TME. Recent treatment strategies incorporating immune-checkpoint inhibitors and anti-angiogenic agents have brought many changes and advances in clinical cancer treatment. However, there are still challenges for immune suppressive tumors, which are characterized by a lack of T cell infiltration and treatment resistance. In this review, we will investigate the crosstalk between immunity and angiogenesis in the TME. In addition, we will look at strategies designed to enhance anti-cancer immunity, to convert “immune suppressive tumors” into “immune activating tumors,” and the mechanisms by which these strategies enhance effector immune cell infiltration.

Inflammation is considered the root cause of various inflammatory diseases, including cancers. Decursinol angelate (DA), a pyranocoumarin compound obtained from the roots of Angelica gigas, has been reported to exhibit potent anti-inflammatory effects. In this study, the anti-inflammatory effects of DA on the MAP kinase and NFκB signaling pathways and the expression of pro-inflammatory cytokines were investigated in phorbol 12-myristate 13-acetate (PMA)-activated human promyelocytic leukemia (HL-60) and lipopolysaccharide (LPS)-stimulated macrophage (Raw 264.7) cell lines. PMA induced the activation of the MAP kinase-NFκB pathway and the production of pro-inflammatory cytokines in differentiated monocytes. Treatment with DA inhibited the activation of MAP kinases and the translocation of NFκB, and decreased the expression and exogenous secretion of IL-1β and IL-6. Furthermore, LPS-stimulated Raw 264.7 cells were found to have increased expression of M1 macrophage-associated markers, such as NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), and the M2 macrophage-associated marker CD11b. LPS also activated pro-inflammatory cytokines and Erk-NFκB. Treatment with DA suppressed LPS-induced macrophage polarization and the inflammatory response by blocking Raf-ERK and the translocation of NFκB in Raw 264.7 cells. Treatment with DA also inhibited the expression of pro-inflammatory cytokines, such as IL-1β and IL-6, NOX, and iNOS in Raw 264.7 cells. These results suggest that DA has the potential to inhibit macrophage polarization and inflammation by blocking the activation of pro-inflammatory signals. These anti-inflammatory effects of DA may contribute to its potential use as a therapeutic strategy against various inflammation-induced cancers.

The regulation of hypoxia-inducible factor-1α (HIF-1α) during endochondral bone formation is not fully understood. Here, we investigated the cross-talk between HIF-1α and Runt-related transcription factor 2 (Runx2) in the growth plate. Runx2 caused the accumulation of HIF-1α protein in ATDC5 chondrocytes and HEK293 cells under normoxic conditions. Runx2 also increased the nuclear translocation of HIF-1α when coexpressed in HEK293 cells and interacted with HIF-1α at the oxygen-dependent degradation domain (ODDD). In addition, Runx2 competed with von Hippel-Lindau tumor suppressor protein by directly binding to ODDD-HIF-1α and significantly inhibited the ubiquitination of HIF-1α, even though Runx2 did not change the hydroxylation status of HIF-1α. Furthermore, overexpression of Runx2 resulted in the significant enhancement of vascular endothelial growth factor (VEGF) promoter reporter activity and protein secretion. Runx2 significantly increased angiogenic activity in human umbilical vein endothelial cells in vitro. In wild-type mice, HIF-1α and Runx2 were colocalized in hypertrophic chondrocytes in which the cluster of differentiation 31 (CD31) protein was expressed at embryonic day 15.5 (E15.5). In contrast, the expression of HIF-1α was markedly reduced in areas of CD31 expression in Runx2(-/-) mice. These results suggest that Runx2 stabilizes HIF-1α by binding to ODDD to block the interaction between von Hippel-Lindau protein and HIF-1α. In conclusion, Runx2, HIF-1α, and VEGF may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation.

Inhibition of angiogenesis is an attractive approach for the treatment of angiogenic diseases, such as cancer. Vascular endothelial growth factor (VEGF) is one of the most important activators of angiogenesis and interacts with the high-affinity tyrosine kinase receptors, VEGFR-1 and VEGFR-2. The pyranocoumarin compounds decursin and decursinol angelate isolated from the herb, Angelica gigas , are known to possess potent anti-inflammatory activities. However, little is known about their antiangiogenic activity or their underlying mechanisms. Here, we show the antiangiogenic effects of decursin and decursinol angelate using in vitro assays and in vivo animal experiments. Decursin and decursinol angelate inhibited VEGF-induced angiogenic processes in vitro , including proliferation, migration and tube formation of human umbilical vein endothelial cells. Decursin and decursinol angelate significantly suppressed neovessel formation in chick chorioallantoic membrane and tumor growth in a mouse model. The microvessel density in tumors treated with decursin for 14 days was significantly decreased compared with a vehicle control group. Decursin and decursinol angelate inhibited VEGF-induced phosphorylation of VEGFR-2, extracellular signal-regulated kinases and c-Jun N-terminal kinase mitogen-activated protein kinases. Taken together, these results demonstrate that decursin and decursinol angelate are novel candidates for inhibition of VEGF-induced angiogenesis.