Antiangiogenic role of natural flavonoids and their molecular mechanism: an update

Angiogenesis is the development of new blood vessels from the existing vasculature, which is important in normal developmental processes. Angiogenesis is a key step in tumor growth, invasion, and metastasis. Angiogenesis is necessary for the proper nourishment and removal of metabolic wastes from tumor sites. Therefore, modulation of angiogenesis is considered a therapeutic strategy of great importance for human health. Numerous bioactive plant compounds are recently tested for their antiangiogenic potential. Among the most frequently studied are flavonoids which are abundantly present in fruits and vegetables. Flavonoids inhibit angiogenesis and metastasis through the regulation of multiple signaling pathways. Flavonoids regulate the expression of VEGF, matrix metalloproteinases (MMPs), EGFR, and inhibit NFB, PI3-K/Akt, and ERK1/2 signaling pathways, thereby causing strong antiangiogenic effects. This present review aimed to provide up-to-date information on the molecular mechanisms of antiangiogenic properties of natural flavonoids. Presently developed antiangiogenic drugs in malignant growth treatment do not meet assumptions about adequacy and safety. So further investigations are needed in this field in the future. More recently, flavonoids are the most effective antiangiogenic agent, by inhibition of signaling pathways.


Background
Polyphenols which are the bioactive compounds derived from natural resources have pulled in a lot of consideration for their well-being advancing impacts. Flavonoids are a significant class of secondary metabolites having a polyphenolic structure, commonly found in natural sources such as vegetables, fruits, and certain refreshments (Table 1) [22]. They have a variety of useful antioxidant and biochemical consequences related to different infections, for example, carcinoma, Alzheimer's problem, and atherosclerosis, among others [23][24][25]. Flavonoids have various medicinal features such as antiinflammatory, neuroprotective, and cardioprotective [26][27][28] activities. A few previous studies showed flavonoids have antiviral and antibacterial properties [29][30][31]. Furthermore, there are a lot of articles that zeroed on the anticancer properties of phenolics [32][33][34]. As of now, flavonoids and their subordinates have been seriously assessed corresponding to malignant growth cell control as well as endothelial cell and angiogenic controllers.
The compounds of flavonoids are present in nature and found in various parts of the plant. Plants used flavonoids for their development and protection oppose plaque [35]. Several flavonoids are simply recognized as pigments of flowers in the majority of families of angiosperm [36]. Flavonoids have numerous subclasses which consisted of flavones, chalcones, isoflavones, and flavonols.
Flavonoids can be classified into different subgroups depending on the carbon of the C ring on which the B ring is bound and the degree of oxidation and unsaturation of the C ring. The third position where the C ring is linked with the B ring is known as flavonoids isoflavones. The fourth position where the C ring is linked with the B ring is known as neoflavonoids. The second position where the C ring is linked with the B ring can be divided into various groups such as flavonols, flavones, flavanonols, catechins, anthocyanins, and chalcone ( Fig. 1) [38]. Angiogenesis is the generation of fresh blood vessels from a prior vasculature [39]. Angiogenesis is fundamental for the development and revival of tissue where it is favorable for a lot of progress including wound healing and embryogenesis [40]. Angiogenesis regulation is difficult and is sustained by the stability within endogenous stimulators (hypoxia-inducible factors (HIFs), plateletderived growth factors (PDGFs), and vascular endothelial growth factors (VEGF)) and inhibitors (endostatin and angiostatin). Subsequently, focusing on angiogenesis has been a helpful methodology for the treatment of various infections. Unregulated angiogenesis may bring about various pathologies [41], for example, diabetic retinopathy [42], rheumatoid joint pain [43], psoriasis, disease development [44], and adolescent hemangiomas [45]. Tumor development and metastasis are angiogenesis subordinates [46]. A developing tumor needs a wide organization of vessels to flexibly supplement oxygen. Furthermore, the new intratumoral veins provide a route for tumor cells to enter the path and to metastasize to far-off organs. Subsequently, every organ framework may include sicknesses in which angiogenesis is a significant factor.
The present literature review article explains the upto-date information about the molecular mechanism of flavonoids and their antiangiogenic properties.

Main text
Flavonoids' impact on different pathways Impact on signaling pathways Intercellular correspondence assumes a key part in the control of cell exercises just as in the association of all cell activities. Signaling communication unbalance can prompt a wide range of obsessive states, inclusive of most cancers and strange tumorigenesis [58]. Hence, focusing on signaling pathways has become a great technique to combat tumorigenesis.

VEGF signaling pathway
Vascular endothelial development factor is a significant supporter of angiogenic factor, applying its cell impacts essentially through the stimulation of vascular endothelial growth factor receptor 1, vascular endothelial growth factor receptor 2, and two tyrosine kinase receptors. The important VEGF receptor on the endothelial surface is VEGFR2. Vascular endothelial growth factor receptor 2 is the principal VEGF receptor on the endothelial cell surface [59]. Not many examinations revealed the significant role of VEGFR2 in lump neovascularization, metastasis, and development [60]. Actuation of VEGFR2 prompts different downstream signals of phosphorylation, for example, p38 mitogen-activated protein kinases (p38MAPK), phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase-1, 2 (ERK 1/2), and AK tymoma protein (AKT), trailed through the initiation of endothelial cells (e.g., multiplication, relocation) [61].

bFGF signaling pathway
Basic fibroblast growth factors are a group of pleiotropic aspects associated with the guideline of different major measures, as well as cell expansion, separation, survival, and angiogenesis [62]. It can also stimulate endothelial cell receptors or actuate the proangiogenic arrivals from different types of cells with ensuing angiogenesis stimulation [63]. In addition, it appears to be that downregulating of bFGF flagging can be associated with protection from VEGF-inhibitor treatment [64]. Presently, in clinical investigations, different types of molecules came to be revealed to interfere with the FGFR/ FGF axis [65].

HIF-1 signaling pathway
The significant controller of oxygen homeostasis in cells presented to hypoxia is HIF-1. This is associated with a wide range of capacities, for example, irritation, cell endurance, and apoptosis [66]. In different types of tumors, hypoxia is a usual component and assumes a HIF-1 key part in the variation of cells to reduce oxygen stress [67]. It can trigger the statement of various supportive factors of angiogenesis, as well as VEGF and its receptors, angiopoietins 1 and 2, platelet-determined development factor, plasminogen activator inhibitor-1, the angiopoietin receptor TIE-2, MMP-2, and MMP-9 [68].

Impact of flavonoids on matrix metalloproteinases
A vascular cellar layer is needed to advance endothelial cell intrusion into the interstitial matrix. This cycle is carried out by MMPs which are also known as proteolytic proteins. As was illustrated, MMP-9 and MMP-2 assume a significant part of angiogenic growth [69]. Several flavonoids were demonstrated to hinder the movement of various MMPs, and it is recommended that this impact may add to their antiangiogenic/anticancer impact.

Molecular mechanism of flavonoids
Naringenin is a type of flavonoid which is abundantly found in tomatoes and oranges. Naringenin has possessed some biological activities like hypolipidemic, hypocholesterolemic, and antagonistic to estrogenic; antihypertensive; and anti-inflammatory exercises. Qunyi et al. [2] reported the antiangiogenic role of naringenin in HUVEC cell lines. The authors revealed that naringenin slowed down a few stages in cell expansion, migration, cell cycle arrest, apoptosis, and tube development of endothelial cells. These impacts were joined by the VEGF inhibition initiated by the intervening of the VEGF/KDR pathway (Fig. 1) [2]. Afterward, Chen et al. [1] reported the antiangiogenic activity of naringenin in HUVEEC and zebrafish. They revealed that naringenin showed potential antiangiogenic activity by inhibiting SIV formation in zebrafish embryos [1].
Kaempferol is a flavonoid that is abundantly found in vegetables, tea, and natural products [70], was additionally found to weaken malignancy neovascularization through interruption of VEGF discharge in human cancer cell lines [71]. Chin et al. [4] studied the antiangiogenic activity of kaempferol in HUVEC cell lines. They revealed that kaempferol fundamentally reduced the VEGF-stimulated HUVEC suitability. Kaempferol set off antiangiogenic action in VEGF-stimulated HUVECs by reducing the VEGFR 2 protein level and kinase action. In addition, they found that kaempferol restrains angiogenic capacity by focusing on VEGF receptor-2, and downregulating the PI3K/AKT, MEK, and ERK pathways in VEGF-stimulated HUVECs (Fig. 2) [4]. Later Hu W-H et al. [3] studied the antiangiogenic activity of kaempferol in endothelial cells. They strongly revealed that kaempferol potentiated the extracellular signal-regulated kinase (Erk), endothelial nitric oxide synthase (eNOS), and VEFGR2 phosphorylation [3].
Chrysin is a flavonoid that is abundantly found in honey, propolis, and passion flowers. Although, accurate mechanisms underlying the biological activities of chrysin are still unknown. Song et al. [5] studied the antiangiogenic activity of chrysin in rat models. They revealed that chrysin significantly reduced VEGF and HIF-α expression levels [5].
Myricetin is a flavonoid that is abundantly found in vegetables, fruits, nuts, berries, and herbs. Santosh et al. [8] studied the antiangiogenic activity of myricetin in HUVECs and CAM assay. They revealed that myricetin repressed the development of freshly structured veins in chicken embryonic organisms and downregulated the outflow of VEGF-A [8]. Later, Kim et al. [7] studied the antiangiogenic activity of myricetin using HUVEC cell lines. They revealed that myricetin significantly reduced angiogenesis by inhibiting signal pathways such as Akt/PI3K/mTOR [7]. Zhou et al. [6] studied the antiangiogenic activity of myricetin. They revealed that myricetin significantly reduced angiogenesis by inhibiting P38K signaling pathway and VEGF/VEGFR2 expression levels [6].
Luteolin is a flavonoid which is abundantly found in natural sources such as celery, broccoli, apples, and carrots. Previous reports showed that luteolin possesses an antiangiogenic activity in different endothelial cells. Sung Wook Park et al. [11] reported the antiangiogenic activity of luteolin in HRMECs. They revealed that luteolin inhibited angiogenesis in HRMECs by reducing VEGF expression through the HIF-1α subordinate system by a blockage of ROS production, and VEGF-induced angiogenesis through managing possibly VEGFR2 signaling pathway [11]. Monira et al. [10] revealed that luteolin suppresses the expression of MMP-1 and MMP-9 genes in UVA and UVB-uncovered human dermal fibroblast cells. Zang et al. [9] studied the antiangiogenic activity of luteolin in gastric cancer. They revealed that luteolin significantly reduced angiogenesis by inhibiting the secretion of VEGF through Notch 1 expression [9].
Epigallocatechin 3 gallate is a flavonoid which is abundantly found in tea, green, white, and black teas. Chen et al. [14] studied the antiangiogenic activity of Epigallocatechin 3 gallate, and they revealed that Epigallocatechin 3 gallate had the option to inhibit the relocation and attack of RCC cells by downregulating MMP-9 and MMP-2. Chen et al. [13] studied the role of antiangiogenesis using Epigallocatechin 3 gallate in HUVEC cell lines. They revealed that EGCG decreased angiogenesis by inhibiting the VEGF, endoglin/smad1 signaling pathways (Fig. 3) [13]. Liao et al. [12] studied the antiangiogenic activity of EGCG in hepatocellular carcinoma. They revealed that EGCG significantly decreased angiogenesis by inhibiting the pathways such as PI3K/AKT/HIF-α/VEGF and ERK1/2 /MAPK [12].
Wogonin is a flavonoid which is abundantly found in Radix Scutellariae, a notable natural agent which has indicated striking anticarcinogenic and chemopreventive limit in different examinations [72][73][74]. Ming Hong et al. [16] reported that wogonin suppresses the action of matrix metalloproteinase-9 and inhibits migration and attack in human hepatocellular carcinoma.
Nobiletin is a flavonoid that is abundantly found in citrus peels. Kim et al. [15] studied the MMP-9 expression in human dermal fibroblasts. They revealed that nobiletin suppresses the MMP-9 expression under PMA stimulation, through the regulation of p38MAPK activity [15]. Lin et al. [75] reported that kaempferol inhibits AP-1 action, decreases MMP-2 expression, and consequently suppresses the interference of SCC4 cells and reveals that kaempferol inhibits ERK1/2 phosphorylation, successfully prompting MMP-2 downregulation [75].
Hesperidin is a flavonoid which is abundantly found in citrus fruits. Lee et al. [17] reported that the flavonoid hesperidin applies an anti-photoaging impact by downregulating MMP-9 expressions through mitogen MAPKdependent signaling pathways.
Herbacetin is a flavonoid which is abundantly found in Rhodiola rosea. Li et al. [19] demonstrated the antiangiogenic activity of herbacetin. They revealed that herbacetin suppressed tumor growth both in vivo and in vitro. Furthermore, they confirmed that herbacetin inhibited tumor angiogenesis by blocking the EGFR-ERK/AKT-MMP-9 signaling pathway (Fig. 5) [19].
Delphinidin is a flavonoid which is abundantly found in fruits, flowers, and leaves of plants. Kim et al. [7] reported the antiangiogenic activity of delphinidin. They found that delphinidin decreases the expression level of HIF-1, which is a VEGF transcription factor. They also revealed that it decreases the HIF-1 expression by blocking the ERK and PI3K/Akt/mTOR/p70S6K signaling pathways (Fig. 6) [20].  Quercetin is a flavonoid which is abundantly found in vegetables and fruits. Lupo et al. [21] studied the antiangiogenic activity of quercetin in HRE cells. They revealed that quercetin decreases angiogenesis by inhibiting the signaling pathways VEGFR2, MEK/ERK, PI3K/AKT, and MEK/JNK [21].

Conclusion
Pharmacological examinations carried out on a few flavonoids in vitro and in vivo tests confirmed that their antiangiogenic impact is mediated through a huge variety of cellular and molecular functions.
Every individual substance of these gatherings can be assessed as a multi-target controller, affecting different segments in various cell transduction pathways.
In conclusion, the data present in the review established the molecular mechanisms of different flavonoids. The present review gave generous details that will highlight advanced examinations by dealing with the existing gaps in the literature concerning the different flavonoids' antiangiogenic activity and the prominence of their upcoming possible therapeutically effective antiangiogenic agents.