Review of Natural Resources With Vasodilation: Traditional Medicinal Plants, Natural Products, and Their Mechanism and Clinical Efficacy

For decades, chronic diseases including cardiovascular and cerebrovascular diseases (CCVDs) have plagued the world. Meanwhile, we have noticed a close association between CCVDs and vascular lesions, such as hypertension. More focus has been placed on TMPs and natural products with vasodilation and hypotension. TMPs with vasodilatory and hypotensive activities are mainly from Compositae, Lamiaceae, and Orchidaceae (such as V. amygdalina Del., T. procuinbens L., M. glomerata Spreng., K. galanga L., etc.) whereas natural products eliciting vasorelaxant potentials were primarily from flavonoids, phenolic acids and alkaloids (such as apigenin, puerarin, curcumin, sinomenine, etc.). Furthermore, the data analysis showed that the vasodilatory function of TMPs was mainly concerned with the activation of eNOS, while the natural products were primarily correlated with the blockage of calcium channel. Thus, TMPs will be used as alternative drugs and nutritional supplements, while natural products will be considered as potential therapies for CCVDs in the future. This study provides comprehensive and valuable references for the prevention and treatment of hypertension and CCVDs and sheds light on the further studies in this regard. However, since most studies are in vitro and preclinical, there is a need for more in-depth researches and clinical trials to understand the potential of these substances.

potassium/calcium channels. The detailed mechanism of action is as follows (Hill et al., 2001;Cole and Welsh, 2011). Figure 1 shows a brief description of the vascular tone changes of VSMs to support our understanding of vasodilatory mechanisms (Alexander et al., 2019a;Alexander et al., 2019b).
pathways for vasodilation or hypotension in rats. Supplementary Table S1 shows the details of studies investigating vasodilation of TMPs. All the discussed TMPs, which were primarily from Composite (17%), were shown in Figure 2A. TMPs mainly displayed vasodilation by acting on eNOS and Ca 2+ channels ( Figure 3A). Most of TMPs, such as V. amygdalina Del., T. procuinbens L., M. glomerata Spreng., K. galanga L., etc., have significant vasodilatory bioactivities in vitro, but the hypotensive efffect of only 40% of TMPs have been investigated in vivo at present, such as G. procumbens, H. cere, Bidens pilosa Linn, etc ( Figure 3A). In addition, some TMPs have significant vasodilation but the mechanistic exploration was insufficient, such as G. procumbens, M glomerata Spreng.
Erigeron breviscapus (EB), as a traditional Chinese medicine, is commonly used for neuroprotection and vascular protection. EB induced relaxation on U44619 (Ca 2+ agonists, EC 50 0.354 mg mL −1 ) pre-contracted aortic rings, which was abolished by glibenclamide (KATP inhibitor) or TEA (KCa channel inhibitor). However, this effect of EB was not affected by endothelial removal or ipiliocin (BKCa inhibitor), BaCl 2 (Kir inhibitor) or 4-AP (Kv inhibitor). These results indicated that the vasodilatory activities of EB are mediated by Ca 2+ and KATP channels, rather than endothelial cells or K + channels (Pan et al., 2008).

Tridax procuinbens L.
The water extract of the leaf from Tridax procuinbens (TP) has been shown to reduce blood pressure, but its mechanism remains unclear. The data showed that TP could significantly relieve the contraction caused by PHE (0.1 μM) and K + (60 mM). TP (10 −9 -10 −5 M) also antagonised the Ca 2+ -induced vasoconstriction in a Ca 2+ -free context by high K + . The activity of TP was repressed by BaCl 2 and apamin (K + channels blockers), L-NAME, indomethacin, atropine, propranolol, and methylene blue; however, it was not affected by glibenclamide, TEA, 4-AP or ODQ (guanylyl cyclase inhibitor). Therefore, this action is intervened by endothelial cells and partial ion channels (Salahdeen et al., 2015).

Bidens pilosa L.
Previous studies have shown that the antihypertensive effect of Bidens pilosa (BP) extract is closely related to its vasodilatory activity. The extract of BP was shown to induce a concentrationdependent vasorelaxation of rat aortas pre-contracted by K + (60 mM, inhibition rate 90% at 1.5 mg mL −1 ) and NE (1 μM, inhibition rate 88% at 1.5 mg mL −1 ) which was significantly inhibited by indomethacin or pyrilamine maleate (histamine-1 inhibitor) (Nguelefack et al., 2005). Furthermore, the extract of BP leaves (10, 20, and 30 mg kg −1 ) decreased SBP by 18.26, 42.5 and 30% in normotensive rats and by 25.77, 38.96 and 28.64% in SHR, respectively. Moreover, it also induced hypotension by 27, 34.13 and 18.73% in salt-loaded hypertensive rats, respectively (Dimo et al., 2003). These results indicated that the effect is concerned with vasodilation.
Gynura procumbens (GP) has been shown to decrease blood pressure by inhibiting the angiotensin-converting enzyme. The present experiments showed that the aqueous extract of GP significantly reduced the contraction induced by angiotensin I and II in rat aortic rings, which was blocked by indomethacin (10 μM) or L-NAME (0.1 μM) (Poh et al., 2013). Moreover, the butanoic fraction of GP (2.5-5 mg mL −1 ) also released the PHE (1 μM)-/K + (80 mM)-induced contractions. GP (i.v., 10-20 mg kg −1 ) also reduced mean arterial pressure in anesthetized rats (Hoe et al., 2011). Therefore, it was suggested that GP causes vasodilation through upregulating eNOS levels.

Ethnomedical evidences suggested that extracts from
Helichrysum have anti-inflammatory and anti-allergic activities and are commonly used to treat renal and cardiopulmonary diseases. The researchers found that the ethanolic extract of Helichrysum ceres leaf (HCE) could relax atropine (1 µM)/NE (1 µM)/K + (20, 80 mM)-induced contractions which was weakened by L-NAME (100 µM) in rat aortic. Furthermore, HCE could cause hypotension in normotensive rats or Dahl salt sensitive hypertensive rats (Musabayane et al., 2008). It was shown that activity of HCE is related to the eNOS levels.

Mikania glomerata Spreng.
Mikania globerata (MG) is mainly used to treat respiratory diseases in Brazil. The aqueous extracts and hydroalcoholic extract (HAE) of MG leaves significantly inhibited the histamine contractions in isolated guinea pig tracheas. HAE also induced relaxation in guinea pig tracheas pre-contracted by histamine (IC 50 0.34 mg mL −1 ), acetylcholine (IC 50 0.72 mg mL −1 ) or K + (IC 50 1.41 mg mL −1 ). Moreover, the dichloromethane fraction of MG could relax the isolated mesenteric vascular or aorta in rats (Soares de Moura et al., 2002). But the mechanism of MG needs more exploration in the future.

Flos chrysanthemi Indici
The ethyl acetate extract from Flos chrysanthemi Indici (FCE, 9.4-150 mg/L) antagonized vasoconstriction induced by PHE (1 μM)/K+ (60 mM), which was significantly inhibited by endothelium removal, L-NAME (10 −4 M), glibenclamide and methylene blue (10 −5 M). But this effect of FCE was not affected by TEA, BaCl 2 , 4-AP, 5-HD or propranolol. In addition, FCE attenuated PHE-induced contraction in calcium-free or potassium-free solutions by upregulated NO levels in rat aortic. Overall, it was showed that FCE is in association with regulation of the NO/cGMP pathway and inhibition of KATP (Jiang et al., 2005).

Others
The hydroalcoholic extract of Senecio nutans sch. Bip and the aqueous extract of Tanacetum vulgare L were shown to relax the PHE/K + /NE-dependent contractions of rat aortic rings in an endothelium-dependent manner (Paredes et al., 2016), (Lahlou et al., 2008). Additionally, the dichloromethane extract of Kaempferia galanga L and the methanol extract from Stevia rebaudiana had shown antihypertensive activity in anaesthetised rats or SHR (Othman et al., 2006;Melis 1995). But the mechanism of these extracts is not sufficiently studied at present.
Hawthorn is used worldwide as traditional medicines to treat CCVDS, such as Crataegus gracilior J. B. Phipps (Mexican hawthorn, MH). The aqueous extracts of the leaves and fruits of MH elicited relaxation of aortic rings treated by PHE (1 µM), and its methanol extract (EC 50 4.34 mg mL −1 ) had significant vasodilator effects (Hernández-Pérez et al., 2014). Additionally, the extract of Crataegus leaves and flowers caused relaxation in PHE (10 mM)-mediated rat aorta (IC 50 15.1 μg mL −1 ) or human papillary artery (IC 50 19.3 μg mL −1 ) from patients undergoing coronary artery bypass surgery. In short, the vasodilation of the extract is concerned with the eNOS pathway, but other pathways need to be further explored (Brixius et al., 2006).
The vasodilation activity of the aqueous extract of Fragaria x ananassa Duch (wild strawberry, WS) leaves attenuated NEinduced (0.1 µM) vasoconstriction in rat aortas which was suppressed by L-NAME or indomethacin. Therefore, similar to the hawthorn aqueous extract, the aqueous extracts could cause endothelium-dependent vasodilation which were correlated with the NO/COX pathways (Hernández-Pérez et al., 2014).

Aronia melanocarpa
The high content of phenolic constituents of Aronia melanocarpa (AM) is characterized by a variety of biological activities.
Researchers have found that AM juice caused potent endothelium-dependent relaxations in porcine coronary artery rings, which was markedly abolished by L-NAME, PP2 (Src kinase inhibitor) and wortmannin. This result showed that AM juice promotes NO levels in the coronary artery endothelium by activating the Src/PI3 kinase/Akt pathway. Its main active components may be conjugated anthocyanins and chlorogenic acid (Kim et al., 2013).

Sorbus commixta Hedl.
The cortex of this species has been used for antitussive purposes in oriental medicine. The methanol extract of Sorbus commixta cortex (SC) produced relaxation of the PHE-induced aorta which was attenuated by L-NAME, methylene blue, ODQ and endothelial removal except for indomethacin, glibenclamide, TEA, atropine or propranolol. Thus, its vasodilatory activity occurs through activation of the NO/cGMP pathway rather than blockage of KCa or KATP (Kang et al., 2005).

Angelica dahurica Bentham
Angelica dahurica Bentham (ADB) has been used for the treatment of CCVDs in Asia. The methanol extract of ADB (1 mg mL −1 ) resisted PHE (1 μM)-/K + (60 mM)-induced contractions in aortic rings but not caffeine (opener of ryanodine-sensitive receptors) in a Ca 2+ -free context (Lee et al., 2015). But the vasodilatory activity of ADB needs further investigation.

Bupleurum fruticosum L.
The studies have shown that Bupleurum fruticosum (BF) is beneficial to the heart and circulatory system. The chloroformic extract of the BF roots (0.1 mg mL −1 ) induced relaxation of rat thoracic aorta induced by NE or caffeine. This activity was blocked by cyclopiazonic acid (Ca 2+ -ATP blocker) (Testai et al., 2005).

Others
The total alkaloids of Sophora alopecuroids L. (SA, 40 mg L −1 ) resisted concentrate induced by K + -/Ca 2+ in rabbit aortas, while was not significantly affected by removal of endothelium, L-NAME, indomethacin or propranolol ). Seeds of Securigera securidaca (SS) were used for the improvement of hyperlipidaemia in Iranian medicine. The hydroalcoholic extract of SS could improve vascular endothelium-dependent relaxation and decrease lipid levels and peroxidation in a rat model fed a high-fat diet (Garjani et al., 2009).
The roots of Salvia miltiorrhiza (SM) is used to treat CCVDS, such as angina pectoris and myocardial infarction in TCM. The aqueous extract of SM relaxed the NA-induced aorta which was abolished by L-NAME (100 μM), methylene blue (10 μM) and endothelium removal. Additionally, SM produced hypotensive response in normal rats through regulating release of angiotensin and bradykinin (Kamata et al., 1993). Moreover, SM caused hypotension in albino rats and rabbits, which was abolished by atropine and propranolol. Interestingly, low concentration of this extract, not higher concentration, induced vasodilation of the renal, mesenteric and femoral arteries (Lei and Chiou, 1986).

Marrubium vulgare L.
The water extract of Marrubium (Ma) showed a potent inhibition on K + -induced rat aorta contractions and decreased SBP by improving endothelial function in SHR (El Bardai et al., 2003). But mechanisms of Ma needs more exploration in vivo or vitro in the future.
The extracts of Allium sativum (AS) induce hypotension in hypertensive patients. AS could relieve NE (3 μM)-induced contractions in the aortic ring which was resisted by L-NAME (100 μM) and indomethacin (5 μM) (Takashima et al., 2017). Thus, the application about AS also needs to be supported by more research in CCVDs.
The hydroalcoholic extract of Alpinia zerumbet leaves (AZ) could resist NE-induced contractions which was not suppressed by indomethacin, 4-AP or glibenclamide except for L-NAME and ODQ (de Moura et al., 2005). The essential oil of AZ (0.01-3,000 mg mL −1 ) also relieved PHE-induced contractions which was inhibited by L-NAME and endothelial removal but not TEA (500 mM) or indomethacin (10 mM) (Pinto et al., 2009). Thus, the activity of AZ is mainly concerned with endothelial cells.

Curcuma comosa Roxb.
Researchers have found that Curcuma comosa Roxb (CC) prevented the impairment of vascular relaxation by regulating the eNOS and ER-α protein levels in aorta of ovariectomised rats (Intapad et al., 2012). Additionally, CC promoted the phosphorylation of serine 1,177 in eNOS and serine 473 in Akt protein (Intapad et al., 2009). CC also improved the diastolic function of the aorta in hypercholesterolemic rats by activation of HSP70 and BCl-2 levels, improving activity of antioxidant enzymes (Kam et al., 2012).

Others
The methanol and water extracts of curcuma herbs such as C. kwangsiensis (1 mg mL −1 ), C. phaeocaulis (1 mg mL −1 ), C. wenyujin (1 mg mL −1 ), and C. zedoaria (1 mg mL −1 ) could relieve prostaglandin F-2α (6 μM)-induced contractions in aortic ring. Additionally, curcuma herbs such as C. zedoaria (3% wt/wt) could lower blood pressure and protect endothelial cells in SHR . Therefore, curcuma herbs, with acivities of invigorating blood circulation and eliminating stasis according to Chinese Medicine, may have significant potential for the prevention and treatment of CCVDs.

Dendrobium officinale Kimura. et Migo.
Dendrobium officinale (DO) has been found to improve metabolic diseases including hypertension and diabetes mellitus. In addition, the extract of DO (3.1 g kg −1 ) significantly reduced SBP and mean arterial pressure in the hypertensive rats. Moreover, it reversed thoracic aortic thickening and endothelial cell apoptosis, decreased plasma ET-1/TXB2 levels and upregulated PGI2/NO levels (Liang et al., 2018).
The methanolic extract of the root bark of Paeonia suffruticosa (PS) showed a vasodilation in rat aortas pre-contracted by PHE (0.3 μM, IC 50 16.8 μg mL −1 ). PS increased the endothelium and SOD function in rats fed a high-fat diet. Therefore, PM elicited vasorelaxant activity by protecting endothelial cells (Yoo et al., 2006).

Nigella sativa L.
Nigella sativa (NS, 2-14 mg mL −1 ) extract induced a dosedependent relaxation in aortic rings treated by PHE (1 μM)/K + (60 mM) which was abolished by diltiazem, TEA and glibenclamide except for L-NAME, indomethacin or ruthenium red (LTCC inhibitor). This finding was suggested that effect of NS is concerned with activating on K + channels (Niazmand et al., 2014).

Ginkgo biloba L.
Ginkgo biloba leaf extract (GB) has been clinically used to improve peripheral vascular disease in France and Germany.
Researchers have found that GB produced a dose-dependent relaxation in aortic rings treated by NE, which was alleviated by L-NAME (100 μM), TEA (100 μM) and indomethacin (100 μM). In contrast, the effects of GB (3 mg mL −1 ) was strongly attenuated to 53% in Ca 2+ -free medium (Kubota et al., 2001), (Nishida and Satoh, 2003). Additionally, GB significantly reduced SBP in rats fed with 8.0% NaCl or SHR and potentiated the relaxation in response to acetylcholine in aortic (Kubota et al., 2006). However, GB was significantly increased serum alanine aminotransferase and hepatic CYP2B protein levels in aged SHR (Tada et al., 2008). It was suggested that the effect of GB was caused by Ca 2+ channels inhibition and NO levels promotion, endothelial cells protection in SHR. Notably, terpenoids and flavonoids may be the main active components of GB (Nishida and Satoh, 2003;Seiichiro and Hiroyasu, 2004).
Loranthus ferrugineus Roxb could be successively fractionated by chloroform, ethyl acetate and n-butanol. n-butanol fraction of LFME (NBF-LFME) produced a significant inhibition of PHE-/ K+-induced aortic ring contractions. Moreover, NBF-LFME lowered blood pressure more compared with the other fractions in normal rats. Thus, the effects of LFME were attributed to content of terpenoids in the n-butanol fraction .

Agelanthus dodoneifolius
The ethanolic extract of Agelanthus dodoneifolius (AD, 0.01-10 mg kg −1 , i,v.) could decrease the systolic and diastolic blood pressure in normotensive rats but not heart rate. Fruther, the extract was divided into 14 fractions (F1-F14). F4, contained most of the dihydropyranone dodoneine, produced the most effective activation (ED 50 160 μg mL −1 ) in NE-induced aortic rings contractions and reduced systolic and diastolic blood pressure by 56.9 and 81.6%, respectively in SHR (Ouedraogo et al., 2011). But the relationship between hypotensive activity and vasodilation of AD needs further investigation in the future.

Morus bombycis Koidzumi
The ethanol extract of Morus bombycis koidzumi (MBK) exhibited vasodilatory effect (IC 50 3.9 μg mL −1 ) which was abolished by L-NAME or endothelial removal in rat aortas. Moreover, MBK extract (10, 30 and 100 mg kg −1 ) dose-dependently reduced SBP and attenuated liver lipid peroxidation and DNA-damage in SHR (Oh et al., 2007a). Therefore, the hypotensive activity of MBK is closely related to vasodilation, but the mechanism of vasodilation needs more exploration.
The major components of Mulberry leaves (ML) are polyphenols, flavonoids, carbohydrates, proteins and lipids. Researchers have found that ML could produce vasorelaxation of aortas treated by high K + (60 mM) or PHE (1 μM) in arteries, which was abolished by ruthenium red (Xia et al., 2007). But mechanistic studies are notably imperfect such as endothelial cells and ion channels.
The extracts of Ficus sycomorus leaves (decoction, macerated and ethanol extract) exhibited a significant vasodilation in rat aortas (IC 50 1.27, 0.38, and 0.13 mg mL −1 , respectively). But the effect of extract was inhibited by L-NAME except for ethanol extract (Ramdé-Tiendrébéogo et al., 2014). Thus, the vasodilatory potential of the extracts needs further exploration in the future.

Other Sources
Sesamum indicum L.

Terminalia superba Engl.et Diels
The aqueous, the methanolic and the methylene chloride extracts from the stem bark of Terminalia superba (TS) induced vasodilation on K + -/PHE-induced contractions in rat aortic rings. In contrast, the effect of TS was endothelium-dependent which was decreased by L-NAME (Tom et al., 2010).
Stephania abyssinica Walp (SA) is used to treat arterial hypertension in west region of Cameroon. A previous study indicated that aqueous (ASAW) and methanol (MSAW) extracts from fresh leaves of S. abyssinica exhibited vasorelaxation by K + -induced contractions (EC 50 0.16, 0.35 mg kg −1 ) in aortic rings. ASAW (EC 50 , 0.18 mg kg −1 ) also resisted contracted by PHE in aortic rings which was affected by TEA, glibenclamide, and propranolol but not L-NAME. These results indicated that the vasodilation of ASAW is mediated by Ca 2+ /KATP channels (Nguelefack et al., 2015).

NATURAL PRODUCTS WITH VASODILATION IN VITRO AND ANTIHYPERTENSIVE ACTIVITIES IN VIVO
This section summarized the vasodilation of natural compounds. Some compounds have significant vasodilation (EC 50 /IC 50 < 10 μM), whose mechanism are related to multi-pathways (Supplementary Table S2). The natural products, mainly flavones (30%), were shown in Figure 2B. Importantly, they showed vasodilation mainly by acting on Ca 2+ channels and eNOS ( Figure 3B).
Additionally, we briefly analysed the structure-activity relationship of the compounds with remarkable functions, as shown in Figure 4. Among the phenolic acids, hexahydrocurcumin and curcumin had the prominent vasodilatory effects. The difference in bioactivity may be related to the number of double bonds. All compounds, specifically flavones, displayed the most excellent potential. To summarise, the vasodilation of these compounds was related to the number and position of double bonds, carbonyls, phenolic hydroxyl groups and methoxy groups. Furthermore, some compounds, such as chrysin glucoside, tilianin, reticuline and hirsutine also exhibited hypotension in vivo ( Figure 3B).

Flavones
Apigenin Apigenin (Ap) was a flavonoid in the Chinese herbal medicine Flos Chrysanthemi that displays anti-hypertensive and antiinflammatory activities. Ap markedly reduced rat thoracic aorta contractions induced by pyrogallol or acetylcholine (pD2 6.56, 5.31), which was weakened by L-NAME rather than aminoguanidine or indomethacin. Additionally, Ap significantly reduced blood pressure of in hypertension rat by ameliorating NO levels and nitrite urinary excretion (Jin et al., 2009).

Formononetin
Formononetin (Fo), as a methoxylated isoflavone, enhanced NO levels or endothelial cell function and also induced vasodilation by K + pre-contractions in rat aortas (EC 50 107.2 μM). This action was reduced by endothelial removal and L-NAME. Moreover, the vasodilatory activity was concerned with the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway .

Baicalein/Luteolin
Baicalein and luteolin were shown to significantly alleviate insulin resistance (IR)-induced SBP elevation which were inhibited by bisphenol A diglycidyl ether in rats fed fructose for 12 weeks. Meanwhile, they also reduced excessive vasoconstriction of PHE/ K + in IR animals through elevating NO/ROS (reactive oxygen species) levels (Huang et al., 2004).

Alkaloids
Harmaline Harmaline (Ha) has shown hypotensive activity in vivo, but the mechanism is no clear at present. Researchers had found that Ha (3, 10, and 30 μM) induce relaxation in aortas pre-contracted by NE/K + , which was significantly suppressed by L-NAME, indomethacin, prazosin (α-adrenoreceptors blocker) or diltiazem. Thus, the effect of Ha was related with activation of the prostacyclin or eNOS pathway (Berrougui et al., 2006).

Sinomenine
Sinomenine acutum Rehder has been used in the treatment of rheumatoid arthritis in China and its extract is also found to have vasodilator activity. Sinomenine (Si, 0.1-10 μM), as the mainly compound from Sinomenine acutum Rehder, produced relaxation in aortic rings pre-contracted by PHE (10 nM) or K + (40 mM) which was attenuated by glibenclamide. Similarly, Si (1-100 μM) also reduced Ca 2+ concentration in aortic smooth muscle (A7r5) cells induced by PHE (1 μM) or K + (40 mM), which was eliminated by glibenclamide. Moreover, Si (i.v. 2.5-10 mg kg −1 ) decreased SBP in SHR . Thus, the activity of Si was concerned with activation of KATP.

Geissoschizine Methyl Ether/Hirsutine
Geissoschizine methyl ether (Ge) and hirsutine resisted NE (10 nM)-induced contractions (EC 50 0.74, 10.6 μM) which were abolished by endothelial removal or L-NAME (100 μM). Furthermore, hirsutine reduced the SBP and heart rate of SHR (Yuzurihara et al., 2002). These results were suggested that the vasodilatory activity of NE is closely related to endothelial cells.

Piperine
Piperine (Pi), as main compound in Sahatsatara formula, had been demonstrated to have hypotensive effects in L-NAMEinduced endothelial dysfunction rats. Moreover, it relaxed the thoracic aorta and has vascular protection effects against hypertension in rats (Booranasubkajorn et al., 2017).

Curine
Curine could inhibit contractions induced by KCl and Bay K8644 in rat aortas and decreased intracellular Ca 2+ concentration in VSMCs. The activity was not abolished by 3-isobutyl-1methylxanthine (phosphodiesterase inhibitor), dibutyryl cyclic AMP (protein kinase A activator) or 8-br-cyclic GMP (protein activator kinase G) (Medeiros et al., 2011). It was indicated that potential of curine is associated with endothelial cells and ion channels.

Paeonol
Paeonol (Pa) is the main component of the Chinese herbs Paeonia suffruticosa Andr. and Cynanchum paniculatum (Bunge) Kitagawa. Pa displayed anti-ischemia reperfusion injury, antihypertensive, anti-platelet aggregation, scavenges oxygen free radicals, antiatherosclerosis and anti-VSMCs proliferation activities. Researchers have found that Pa relaxed PHE-induced isolated rat aortic rings (EC 50 290 μM). Additionally, Pa significantly inhibited vasoconstriction induced by angiotensin II, prostaglandin F-2α, 5-HT, dopamine, vasopressin and endothelin-1. Moreover, the activity of Pa was not affected by L-NAME, ODQ, propranolol, glibenclamide, TEA and BaCl 2 in the rings. Therefore, the vasodilatory effect of Pa was in relationship with regulation of Ca 2+ channels (Li et al., 2010).

Sodium Ferulate/Ferulic Acid
Ferulic acid (Fa) was the main component of Radix Angelicae Sinensis and Rhizoma Chuanxiong. Studies have shown that sodium ferulate (Sf) or Fa displayed anti-platelet aggregative, anti-inflammatory, antioxidative activities. Sf relaxed the aortic rings pre-contracted with PHE/K + (pD2 2.7 and 2.6, respectively), which was no affected by TEA, glibenclamide, 4-AP and BaCl 2 . Sf also inhibited contraction in K + /PE/PMA pre-contracted rings in Ca 2+ -free solution (Chen G. et al., 2009). Moreover, Fa decreased superoxide anion levels in SHR aortas and improved acetylcholine-induced vasodilation in SHR but not in WKY rats (Suzuki et al., 2007). This activity was related to the methoxy modified 3-position in the benzene ring and 2propylene (Fukuda et al., 2015).

Ellagic Acid
Ellagic acid (Ea), a polyphenolic compound, has antihypertensive, anti-diabetic, anti-oxidantive, anti-inflammatory and anti-hyperlipidaemia effects. Ea relaxed the aortic pre-contracted by PHE (pD2 5.60), which was partially abolished by endothelium removal and L-NAME rather than indomethacin. Therefore, the activity of Ea was related to endothelium cells and Ca 2+ channels (Yılmaz and Usta, 2013).

Astragaloside IV
Astragalus membranaceus has been used to treat and prevent CCVDs such as haemorrhagic stroke and viral myocarditis. Astragaloside IV (As-IV), the main component of A. membranaceus, has anti-cardiac hypertrophy, antiinflammatory and anti-oxidant activities. As-IV could antagonise contractions induced by PHE/K + in aortic rings from normal rats and SHR. Similarly, As-IV attenuated the vasoconstriction induced by angiotensin II or PHE in presence of perivascular adipose tissue . This activity of As-IV was abolished by L-NAME or ODQ rather than 7nitroindazole (neuronal eNOS inhibitor). Therefore, this vasodilatory was associated with blockage of calcium channel, and activation of NO/cGMP pathway (Zhang et al., 2007). Additionally, As-IV (orally, 40-80 mg kg d −1 ) improved the expression of eNOS, SOD and GSH-Px in the thoracic aorta and decreased ROS levels in a streptozotocin-induced diabetic rat model. It was suggested that As-IV ameliorates endothelial damages in the thoracic aorta of diabetic rats via regulating levels of ROS and calpain-1 (Nie et al., 2019).

Jujuboside B
Zizyphi Spinosi Semen (ZSS) has protective effects against myocardial ischemic injury and hypertension. Jujuboside B (Ju), obtained from ZSS, reduced the tension of rat aorta with intact endothelium. However, the vasodilatory activity of Ju was attenuated by L-NAME, KN93, EGTA, SKF96365, iberiotoxin and glibenclamide rather than indometacin. Therefore, Ju displays its vasodilation through promoting eNOS levels and inhibiting K + /Ca 2+ channels (Zhao et al., 2016).

Glucosyl hesperidin
Researchers have found that hesperidin possessed anti-oxidant, anti-hypertensive. Moreover, glucosyl hesperidin (Gh) has antihypertensive effects and improves lipid metabolism. Gh (50 mg kg d −1 , orally) could reduce blood pressure in SHR and enhance endothelium-dependent vasodilation induced by acetylcholine. Additionally, Gh improved endothelial function by inhibiting the expression of nicotinamide adenine dinucleotide phosphate oxidase in SHR aorta (Yamamoto et al., 2008).

Sesquiterpenoids
Zerumbone resisted aortas contracted by K + (60 mM, IC 50 16 μM) (Fusi et al., 2015). Sesquiterpenoids [curcumanes A, B, C, and (±) D], which were isolated from Curcuma longa, also have significant vasodilation. They could significant resist KClinduced aortic contractions in rats (EC 50 2.40,0.91,6.61,14.56,and 16.03 μM, respectively) and curcumanes A, B, and C also inhibited PHE-induced aortic ring contractions in rats (EC 50 3.37, 0.83, and 4.26 μM, respectively). Additionally, curcumane C promoted the growth of human umbilical vein endothelial cells, which was inhibited by L-NAME. Curcumanes A and B produced vasodilation through regulation of VDCC and ROCC . Therefore, sesquiterpenoids with significant activities should be paid more attention in the prevention and treatment of CCVDs.

Imperatorin/Isoimperatorin
Imperatorin and isoimperatorin were shown to relax rat aorta contractions by PHE. The effect of imperatorin was significantly stronger than that of isoimperatorin. However, this activity was inhibited by endothelial removal and L-NAME (Nie et al., 2009).

Others
Perillaldehyde Perillaldehyde (Pe), is major compound from aqueous extract of Perilla leaves, improves NO levels in VSMCs. Pe (0.01-1 mM) also resisted aorta contraction by prostaglandin F-2α or NE, which was weakened by L-NAME, endothelial removal, propranolol, theophylline, TEA or glibenclamide. Therefore, the vasodilatory effect of Pe was concerned with blockage of Ca 2+ channel (Takagi et al., 2005). Further, Pe (150 mg kg −1 ) reduced aortic atherosclerotic plaques, improved endothelial function, increased tetrahydrobiopterin and NO levels in carotid arteries of mice and rats fed high-fat diet (Yu and Liu 2018).

Phthalides
Ligusticum chuanxiong is used for CCVDs to promote the circulation of blood and removed stasis in TCM. Ligustilide (Li), main phthalides of L. chuanxiong, was used to treat CCVDs. Li was shown to relax rat mesenteric arteries pretreated by KCl, CaCl 2 , NA or 5-hydroxytryptamine (5-HT). But the activates was not affect by propranolol, glibenclamide, TEA and BaCl 2 . It was indicated that Li induces vasodilation through regulating VOCC and ROCC rather than endothelial cells (Cao et al., 2006). Further, the recent research found that the activity of phthalide dimers was generally superior to that of monomeric phthalides. Phthalides dimers, such as Chuanxiongdiolides R4 and R6, inhibited KCl-induced (60 mM) vasoconstriction. Moreover, Chuanxiongdiolides R4 and R6 also significantly inhibited the LTCC subunit α-1c (Cav1.2) (Tang et al., 2020).

Piceatannol
Piceatannol (Pi) caused relaxation in aortas pre-contracted by PHE (EC 50 2.4 μM). This effect was reduced by endothelial removal, L-NAME, methylene blue, ODQ, 4-AP and TEA rather than indomethacin, atropine, propranolol, nifedipine, BaCl 2 or glibenclamide. Moreover, charybdotoxin and iberia toxin (BKCa channel blockers) could also reduce the activity of Pi. Therefore, this vasodilation of Pi may be related to the activation of BKCa and NO pathway (Oh et al., 2007b).

Brazilin
Studies have found that brazilin (Br) has anti-diabetic, antiinflammatory, anti-asthmatic, anti-platelet aggregation, antitumour and anti-oxidant. Further, Br resisted the NE/K +induced contraction of aortic rings (EC 50 83.51 and 79.79 μM, respectively), which was significantly attenuated by endothelium removal, L-NAME, methylene blue or indomethacin. Thus, the activity of Br was related to inhibition of ERK1/2 phosphorylation or blockage of Ca 2+ channels (Yan et al., 2015).

Tanshinone IIA
Tanshinone IIA (Tan IIA) could reduce infarct area and blood pressure in hamsters. Moreover, Tan IIA caused endotheliumdependent relaxation, which was blocked by oestrogen receptor antagonist ICI 182 and 780. Therefore, the activity of Tan IIA was related to oestrogen receptor, NO channels and ERK1/2 phosphorylation (Fan et al., 2011).
Caracasanamide Caracasanamide (i.v.) was shown to reduce blood pressure and increase cardiac muscle strength, respiratory rate and tidal volume in rats. Additionally, it also induced vasodilation in rats through acting on cardiac β1-adrenergic receptors (Delle Monache et al., 1993).

Others
Other lignans (saucerneol, saucerneol D and machilin D) exhibited vasodilation in rat aortic treated by PHE (10 μM, EC 50 2.2, 12.7 and 17.8 μM, respectively). The activities were significantly inhibited by L-NAME or endothelial removal. Additionally, saucerneol and sacerneol D were shown to significantly reduce left ventricular pressure (Oh et al., 2008).

Clinical Application
We also summarized the clinical applications of TMPs and natural products with vasodilatory activies (Figure 5). TMPs and natural products, listed in Figure 5, were mainly used in the treatment of diabetes, hypertension, hyperlipidaemia, and some encephalopathy, which demonstrated the relationship between the vasodilatory activity and the treatment of CCVDs. Some TMPs, such as M. Vulgare and Nigella sativa, etc, combined with conventional therapeutics improved the efficacy and tolerability of the drugs, and reduced their adverse reactions and side effects.
Other TMPs, such as such as Hibiscus sabdariffa L, showed obviously antihypertensive effect. However, the detailed analysis of the drug's underlying mechanism was not performed. In this present study, the role of TMPs and natural products in the prevention and treatment of CCVDs was positive and encouraging, but there were serious limitations in the druggability studies of this field due to lack of researches on toxicology and pharmacokinetics of TMPs and natural products with vasodilatory actives.

Diabetes
In addition to the medical treatment with glbenclamide, the patients suffering from Ⅱ diabetes were treated with M. vulgare (Ma, 3 weeks  (Panahi et al., 2017). Nigella sativa (NS) (Kaatabi et al., 2015), Artemisia herba alba asso (AH) (Al-Waili 1986) and Coriandrum sativum (Cs) (Waheed et al., 2006) can significantly reduce fasting blood glucose in type Ⅱ diabetes. Furthermore, NS could significantly reduce fasting blood glucose, glycated hemoglobin and glutathione, but also improve the levels of total antioxidant capacity, SOD, catalase and glutathione.

Encephalopathy
Ginkgo biloba extract (GB, 120 mg d −1 , 52 weeks) improved cognitive performance in dementia patients and improved ADAS-Cog, GERR and CGIC scores in patients. In addition, GB leaves also improved the prognosis with acute ischemic stroke and increased the NIHSS score in patients. GB leaves (240 mg d −1 , 3 months) could improve memory and attention in senile Alzheimer's disease (Bars et al., 1997;Maurer et al., 1997;Oskouei et al., 2013). Coriander (Co, 4 weeks) also relieved migraine compared with control group by the Akaike criteria (Mansouri et al., 2015).

CONCLUSION
This review discussed TMPs and natural products with vasodilation in vitro. Their possible mechanisms and clinical application were also summarised. Notably, TMPs with vasodilation are mainly from Compositae while natural products are flavonoids. The vasodilatory function of TMPs and natural products is mainly attributed to regulation of eNOS or Ca 2+ channels. Further, we analysed briefly the structure-activity relationship of the compounds with significant vasodilatory effects. The vasodilation of the natural compounds was related to the number and position of double bonds, carbonyls, phenolic hydroxyl groups, and methoxy groups. Overall, these evidences suggested that TMPs and natural products are emerging alternatives for the prevention or treatment of CCVDs such as hypertension. It was foreseeable that they will receive more attention in the future, although there were still some limitations based on literatures. Firstly, the current thoracic aortic models were usually used as the main mode to investigate the vasodilation, whereas different vessels, such as cerebral artery, abdominal aorta and mesenteric artery, have not sufficiently explored (Pfaltzgraff and Bader 2015). Secondly, the various channel blockers, such as TEA, BaCl 2, and 4-AP had been applied to block K + channels. However, the relationship between the vasodilation of TMPs and natural products and other, such as KCNQ, TRPC, and TACC, had not been adequately investigated. Therefore, the underlying mechanisms, especially in relationship with various types of ion channels such as KCa, should be further explored. Thirdly, the clinical researches on the vasodilatory activity of TMPs and natural products is severely insufficient in this regard, although they exhibited remarkable potential in animal models. In addition, current the clinical studies on TMPs and natural products also have some deficiencies. For example, mechanisms of action usually remain unknown and only a small number of patients had been reported in almost all the related literatures. Finally, the application of TMPs is troublesome owing to difficulties in source identification, active ingredients, quality standard and mechanism study. Generally, natural products always maintain unsatisfactory druggability owing to their poor oral bioavailability, low plasma concentrations and so on. The ingested natural products was either excreted unabsorbably or metabolized rapidly after absorption, such as apigenin (Tang et al., 2017), sinomenine (Chen W. et al., 2009) andKaempferol (Calderón-Montaño et al., 2011), etc. However, developments in technologies such as metabolomics, proteomics and genomics will facilitate the application of TMPs and natural products in the treatment of CCVDs (Harvey et al., 2015). The bioavailability of natural products will be greatly improved by amelioration of hydrophilicity or alteration of administration modes. For instance, the curcumin nanoparticles with higher hydrophilicity achieved by loading into sophorolipid micelles had an appreciably higher bioavailability than that of free curcumin crystals (Peng et al., 2018). In addition, compared to oral administration, nasal administered paeonol was absorbed rapidly in rats (Adki and Kulkarni, 2020). The bioavailability of intravenous injection of cinnamaldehyde was also superior to that of oral administration (Zhu et al., 2017), etc.
In brief, we are still optimistic about the prospect of TMPs and natural products. TMPs will be used as alternative drugs and nutritional supplements, while natural products will be considered as potential therapies for CCVDs in the future. This study provides comprehensive and valuable references for the prevention and treatment of hypertension and CCVDs and sheds light on the further studies in this regard. In the next few years, it is necessary to investigate absorption, distribution, metabolism, and excretion of TMPs and natural products with vasodilation in vivo. Also, the activities of the major metabolites of these natural resources should be concerned.

AUTHOR CONTRIBUTIONS
FT contributed to the drafting of the manuscript. Others were involved in searching, screening the search results, translation, and Frontiers in Pharmacology | www.frontiersin.org April 2021 | Volume 12 | Article 627458 18 Tang et al.