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The American Journal of Chinese Medicine, Vol. 42, No. 1, 61–77 © 2014 World Scientific Publishing Company Institute for Advanced Research in Asian Science and Medicine DOI: 10.1142/S0192415X14500049

Therapeutic Angiogenesis after Ischemic Stroke: Chinese Medicines, Bone Marrow Stromal Cells (BMSCs) and their Combinational Treatment Qian Zhang and Yong-Hua Zhao State Key Laboratory of Quality Research in Chinese Medicine Faculty of Chinese Medicine, Macau University of Science and Technology Macao 999078, Macao SAR of P. R. China

Abstract: Ischemic stroke is a clinical acute disease which causes neurological dysfunction and threatens a patient’s life. Because the mechanism of pathology is complicated and most patients miss the best therapeutic window time, the effect of the treatment is not satisfied at present. Numerous studies indicated new vessels not only recuperated blood flow in the ischemic boundary zone, but also facilitated endogenous neurogenesis and improved neurological function after ischemic stroke. Therefore, angiogenesis has been an important research field in neurovascular regeneration. Recently, some Chinese medicines, bone marrow stromal cells (BMSCs) and their combination treatment were demonstrated to have beneficial effects in promoting angiogenesis both in vitro and in vivo. In this review, we summarized the effective mechanisms of Chinese medicines and BMSCs, as well as BMSCs in combination with Chinese medicines on angiogenesis post-stroke. Keywords: Angiogenesis; Bone Marrow Stromal Cells; Chinese Medicines; Combination Treatment; Ischemic Stroke; Review.

Introduction Ischemic stroke is a kind of serious cerebrovascular thrombotic disease, which occludes cerebral blood flow, causes permanent neurological dysfunction and even threatens the patient’s life. In 2008, a report from the World Health Organization (WHO) showed that the percentage of cerebrovascular mortality was 10.8% worldwide and stroke was in the top five causes of death in both low-income and high-income countries (World Health Organization, 2008). At present, recombinant tissue plasminogen activator (rt-PA) was the Correspondence to: Dr. Yong-Hua Zhao, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macao 999078, Macao SAR of P. R. China. Tel: (þ853) 8897-2702, Fax: (þ853) 2882-5123, E-mail: [email protected]

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only drug approved by United States Food and Drug Administration (FDA) for dissolving thrombus and improving the cerebral flow (Adams et al., 1996, 2003), but because the majority of patients miss the therapeutic time window (3  6 h), the therapeutic effect on ischemic strokes is still not satisfied. Recently, more and more studies have focused on neurogenesis and angiogenesis as potential restorative mechanisms after cerebral ischemia. As new vessel formation after ischemic stroke might (1) contribute to recovery of tissue-atrisk by restoring metabolism in surviving neurons; (2) facilitate removal of necrotic debris; (3) enhance neurotrophic components for neuronal remodeling (e.g. synaptogenesis and neurite sprouting); and (4) promote endogenous neural stem cells (NSCs) migration into the ischemic infarction zone to supply the material and energy for neurogenesis, angiogenesis has been recognized to be the basis and prerequisite for neurogenesis (Manoonkitiwongsa et al., 2001; Zhang and Chopp, 2002; Hayashi et al., 2006; Slevin et al., 2006; Arai et al., 2009; Beck and Plate, 2009). Angiogenesis is defined as the growth of new vessels from existing vessels, which is a normal and vital process in tissue growth and development (Folkman, 1971; Bergers and Benjamin, 2003; Seevinck et al., 2010). It may also occur under pathological status, such as post-stroke (Zhang et al., 2011a). In the central nervous system, angiogenesis results in the restoration of cerebral blood flow in the ischemic penumbra, which contributes to the long-term functional recovery after ischemic stroke (Jaquet et al., 2002). A report showed patients with high cerebral blood vessel density survived longer than those with low vascular density (Krupinski et al., 1994). Therefore, it is of great significance to promote angiogenesis in the cerebral ischemic boundary zone (IBZ). Recently, some Chinese medicines, bone marrow stromal cells (BMSCs) and their combination treatment were demonstrated to have a beneficial effect on promoting angiogenesis either in vitro or in vivo. In this review, we aimed to summarize the mechanisms of Chinese medicines and BMSCs, as well as BMSCs combining with Chinese medicines on mediating angiogenic factors (Table 1) and enhancing angiogenesis post-stroke. Table 1. Chinese Medicines, BMSCs and their Combination Treatment Mediate Angiogenic Factors after Ischemic Stroke Angiogenic Factors Vascular endothelial growth factor (VEGF)

Medicines/Cells Ferulic acid Cornel iridoid glycoside (CIG) Ginsenoside-Rg1

Puerarin Astragaloside IV 8-O-acetyl Shanzhiside Methylester (ND01) Catalpol Buyang Huanwu Decoction (BHD)

References Lin et al., 2010 Yao et al., 2009 Yang et al., 2012 Wang et al., 2011a Yin et al., 2011 Leung et al., 2006 He et al., 2011 Li et al., 2011 Jiang et al., 2010 Zhu et al., 2010 Cai and Liu, 2010 Cai et al., 2007

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Table 1. (Continued) Angiogenic Factors

Medicines/Cells

Naomaitong Compound Salvia Tablet

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Kangnao liquid II Tongxinluo (TXL)

Resveratrol Astragalus injection BMSCs Combination of BMSCs and NaomaiYihao Combination of BMSCs and TXL Combination of BMSCs and BHD Combination of BMSCs and astragaloside IV Platelet-derived growth factor (PDGF) Ferulic acid Ang-1 Kangnao liquid II BMSCs Puerarin Buyang Huanwu Decoction (BHD) 8-O-acetyl Shanzhiside Methylester (ND01) Ang-2 Puerarin Hypoxia-inducible factor (HIF-1) Ginsenoside-Rg1

Endothelial nitric oxide synthase (eNOS)

Astragalus injection Astragaloside IV Naomaitong

Ginsenoside-Rg1 Resveratrol Matrix metalloproteinase (MMP) Naomaitong Resveratrol Combination of BMSCs and TXL Basic fibroblast growth factor (bFGF) Compound Salvia Tablet BMSCs Stromal-derived factor-1 (SDF-1) BMSCs Combination of BMSCs and Astragaloside IV

References Chen, 2009 Yin and Wu, 2012 Liu et al., 2011 Yu et al., 2011 Zhu and Yang, 2007 Liang et al., 2011a Yuan et al., 2007 Mei et al., 2006 Yang et al., 2009 Chang et al., 2012 Simão et al., 2012 Liang et al., 2011b Deng et al., 2010 Guo et al., 2012 Hu et al., 2011 Zhang et al., 2010 Wang et al., 2011b Lin et al., 2010 Liang et al., 2011a Zacharek et al., 2007 He et al., 2011 Yin and Wu, 2012 Jiang et al., 2010 He et al., 2011 Wang et al., 2010 Tang et al., 2011 Liang et al., 2011b Zhang et al., 2011b Gao et al., 2006 Chan et al., 2009 Simão et al., 2012 Li et al., 2006 Simão et al., 2012 Hu et al., 2011 Yu et al., 2011 Salvucci et al., 2002 Salvucci et al., 2002 Wang et al., 2008 Wang et al., 2011b

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Chinese Medicines Mediate Angiogenic Factors to Promote Angiogenesis after Ischemic Stroke

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Traditional Chinese Medicine (TCM) has accumulated rich clinical experiences in the prevention, treatment and rehabilitation of ischemic stroke. Recent reports have indicated that some active compounds derived from Chinese material medica or Chinese Medicine formulas, which had the effects of blood-tonifying and activating ( ), replenishing qi ( ), yin-tonifying ( ) and heat-clearing and detoxifying ( ), could improve angiogenesis by mediating angiogenic factors after ischemic stroke. Vascular Endothelial Growth Factor (VEGF) VEGF is an endothelial cell-specific mitogen, which is considered to be an important factor to promote angiogenesis (Perou et al., 2000). It can regulate angiogenesis through multiple ways, including dissolving the extracellular matrix (ECM) of endothelial cells, mediating endothelial cell migration, proliferation and lumen formation, etc. The number of new blood vessels is closely related to the expression of VEGF (Suhantja and Hofman, 2003). Tyrosine protein kinase is activated when VEGF combines with its receptors. This combination will further catalyze the phosphorylation on tyrosine residues, make the information transmission, induce endothelial cell proliferation, migration and cell interactions, and finally promote the formation of new blood vessels. As a sodium salt of Ferulic acid (FA) derived from Radix Angelica sinensis, sodium ferulate (SF) had been demonstrated as a potential pharmaceutic component for neurodegenerative disease, cardiovascular disease, diabetes and other age-related diseases (Barone et al., 2009; Wang and Ou-Yang, 2005; Ramar et al., 2012; Sultana, 2012). Zhou and colleagues reported that SF could promote the recovery of neurological function after cerebral ischemia via reducing infarction volume and cerebral edema, which might be related to the angiogenesis enhancement (Zhou et al., 2006). Most recently, it was reported that SF could inhibit platelet activation in acute cerebral infarction (ACI), modulate the endothelium function, increase brain blood circulation and improve the clinical therapeutic effect (Zhou et al., 2011). Previously, FA was also demonstrated to have the effects of promoting neovascularization in vivo and inducing significant angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro without cytotoxicity, and this is associated with the expression enhancement of VEGF and platelet-derived growth factor (PDGF) in HUVECs (Lin et al., 2010). Cornel iridoid glycoside (CIG) is an active compound derived from Asitatic cornelian cherry fruit. As a potential pharmaceutical candidate for the treatment of stroke, CIG could promote neurogenesis and angiogenesis and improve neurological function after ischemia in rats by increasing VEGF and Flk-1 expressions in the brain (Yao et al., 2009). There were at least four possible splice variants of VEGF, which included VEGF121, VEGF165, VEGF189 and VEGF206 (Ferrara et al., 1992). VEGF165 and VEGF121 were possibly the most abundant isoforms, and mediated a large number of VEGF biological activity. A research showed that CIG could increase the mRNA expression of VEGF165 and

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VEGF121, as well as their receptor Flk-1 in 7 days after middle cerebral artery occlusion (MCAo). Moreover, the expression of VEGF165 was more prominent. CIG also could elevate the level of VEGF protein in the cortex compared with vehicle-treated ischemic rats in 7, 14 and 28 days after ischemia (Yao et al., 2009). Ginsenoside Rg1 could promote angiogenesis in the functional recovery of myocardial infarction, diabetes and neonatal hypoxic-ischemic brain injury in a rodent model. The mechanism was related to the expression of VEGF (Wang et al., 2011a; Yin et al., 2011; Yang et al., 2012). Research had shown that Ginsenoside Rg1 had an obvious protective effect on apoptosis caused by cerebral ischemia reperfusion injury in rats (Hu et al., 2006). Further studies showed Ginsenoside Rg1 was a potent stimulator of VEGF expression in HUVECs, and this induction was mediated through a phosphatidylinositol 3-kinase (PI3K)/Akt and-catenin/T-cell factor-dependent pathway, which resulted in an increase in the level of-catenin, culminating its nuclear accumulation, and subsequent activation of VEGF expression (Leung et al., 2006). Puerarin, an isoflavone, is the main active ingredient in pueraria with oxygen free radicals and anti-apoptosis activity (Jin et al., 2001; Cao et al., 2002). Clinical studies showed that a puerarin injection could benefit microcirculation and improve tissue oxygen supply in the brain (Zhou and Liu, 2011). He et al. (2011) found that puerarin could significantly improve neurological behavior, increase microvessel density (MVD) and the expression of VEGF, angiopoietins (Ang-1 and Ang-2) in a cerebral ischemia-reperfusion (CIR) model in rats. It indicated that puerarin could relieve CIR injury, which mechanism had a relationship with promoting angiogenesis. Astragaloside IV is one of the main active constituents of Astragalus. It had the effect of decreasing the whole blood viscosity, dilating vessels, accelerating the blood stream, decreasing blood lipid, improving microcirculation and so on (Xu and Wang, 2006; Guo et al., 2007). Li and colleagues’ research results showed that Astragaloside IV could improve the neurological function in rats after CIR, which might be related to the upregulation of VEGF protein and MVD in hippocampal region (Li et al., 2011). 8-O-acetyl Shanzhiside Methylester (ND01) is an iridoid glucoside isolated from the leaves of Lamiophlomisrotata (Benth) Kudo, which is a Chinese folk medicinal plant in Xizang (Tibet). For thousands of years, Lamiophlomisrotata had been used as one of the traditional drugs to alleviate pain, detumescence and haemostasis, and reinforce marrow and promote blood circulation (Yi et al., 1997). The study showed that ND01 increased the expression of VEGF, Ang-1 and phosphorylation of Tie2. A recent report indicated that it could significantly promote the angiogenesis of ischemic tissue and functional outcome after stroke (Jiang et al., 2010). Catalpol is an effective compound extracted from Rehmanniae, which can promote angiogenesis in the cortex surrounding of cerebral ischemic rat as well as decrease cerebral vascular endothelial cell swelling. Further research indicated catalpol could increase secretion of endogenous VEGF and activate Erythropoietin to improve neurological function, nerves and blood vessels remodeling, angiogenesis and reduce edema of the brain microvascular endothelial cells after cerebral infarction (Zhu et al., 2010).

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BuyangHuanwu Decoction (BHD) is a commonly used prescription of the TCM therapy for stroke. The researchers found BHD could improve neurological function and quality of life, as well as increase VEGF expression in cerebral infarction patients in a clinical trial (Cai and Liu, 2010). Clinical study showed that BHD could effectively increase the serum VEGF level in ACI patients and facilitate angiogenesis (Chen, 2009). Further study showed that BHD could promote angiogenesis in ischemic brain tissue by up-regulating the expressions of VEGF and Ang-1 (Yin and Wu, 2012). Cai and colleagues (2007) found BHD and its herbal components significantly improved the neurological behavior performances and reduced the infarction volume in the ischemic brain, which were associated with stimulating the proliferation of neural progenitors and the enhancement of VEGF and Flk expressions. Naomaitong (composition of Rhubarb, Ginseng, Chuanxiong and so on) could protect brain damage after focal CIR in the aged rats. Nervous symptoms, oedema of brain, infarct size, morphology and superfine structure of brain in the treated group were better than those of the untreated group (Ren et al., 2004). Liu and colleagues’ experimental result (Liu et al., 2011) indicated Naomaitong could promote angiogenesis after CIR and this might be related to the VEGF/Receptor system. Compound Salvia Tablet was mainly composed of Radix Salviae Miltiorrhizae, Radix Notoginseng, borneol and so on. A recent study indicated that Compound Salvia Tablet could obviously improve the neurological function, reduce the infarct size, increase expression of VEGF and basic fibroblast growth factor (bFGF), promote the establishment of collateral circulation in ischemic cerebral tissue in ACI rats (Yu et al., 2011). Zhu and colleagues found that Compound Salvia Tablet could increase the expression of VEGF in a rat brain during chronic cerebral ischemia, and they proposed that this regulation should play an important role in the chronic cerebral ischemia (Zhu and Yang, 2007). Another similar experiment also indicated Kangnao liquid II could increase the expression of VEGF and Ang-1. It could promote tissue angiogenesis, neuro-function recovery and neurons survival in rats with CIR injury (Liang et al., 2011a). Additionally, Tongxinluo (TXL) could reduce neuron apoptosis rate and enhance angiogenesis in MCAo rat via inhibiting Caspase-3 and p53 activated and promoting the expression of VEGF (Mei et al., 2006; Yuan et al., 2007; Yang et al., 2009; Chang et al., 2012). Hypoxia-Inducible Factor (HIF-1) HIF-1 is the key transcription regulator for multiple angiogenic factors including VEGF. It can regulate gene expression, angiogenesis and other biological effects in order to maintain a stable internal environment to against hypoxia. Ginsenoside-Rg1 could increase the expression of HIF-1 and CD31 of myocardium and stimulate the angiogenesis in acute myocardial infarction (AMI) rats (Wang et al., 2010). Ginsenoside-Rg1 was also recognized to be a potential regulator of HIF-1 expression in Hypoxia/ischemia brain damage (HIBD). Since HIF-1 was a key transcription factor involved in the neuro-protective response to HIBD, Tang and colleagues (2011) proposed that Rg1 could facilitate the process of brain repair, which included cells

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survival, angiogenesis and neurogenesis after HIBD by targeting HIF-1. Another study also confirmed that Ginsenoside-Rg1 is an effective stimulator of HIF-1 under normal cellular oxygen conditions in HUVECs. So research reports demonstrated that HIF-1 protein synthesis could be stimulated by Rg1. This effect was associated with constitutive activation of PI3K/Akt and its effector p70 S6 kinase (p70S6K), but not with extracellularsignal regulated kinase 1/2 (ERK1/2). Further research revealed that HIF-1 induction triggered the expression of target genes, including VEGF (Leung et al., 2011). Studies suggested that the Astragalus injection could significantly protect the cranial nerve in ischemic penumbra around CIR tissue in rats by up-regulating the expression of HIF-1 and VEGF (Liang et al., 2011b). Another study also confirmed that Astragaloside IV could stimulate cell migration, increase tube formation, angiogenesis in the chick chorioallantoic membrane assay and HIF-1 accumulation via PI3K/Akt pathway (Zhang et al., 2011b). Endothelial Nitric Oxide Synthase (eNOS) NO (Nitric oxide), which has the effect of regulating angiogenesis factor and stimulating angiogenesis, is a downstream mediator of many vascular growth factors (Babaei et al., 2003). NO has a dual effect on cerebral ischemia, and this difference should be attributed to hypoxic-ischemic process and sources. Reports indicated that NO generated by eNOS produced the effect of neuroprotection; while NO derived from the overexpression of neuronal NOS (nNOS) and inducible NOS (iNOS) exhibited a neurotoxicity effect (Nakashima et al., 2003; Hashiguchi et al., 2004). So it is necessary to selectively control different types of NOS expression. Ginsenoside-Rg1 could down-regulate miR-214 expression in HUVEC and lead to an increase in eNOS expression. It was possible to promote angiogenesis by enhancing cell migration and tube formation in vitro (Chan et al., 2009). The dominance of Rg1 could increase angiogenesis through the expression of NOS and PI3K/Akt pathway, whereas Rb1 indicated an opposing effect by inhibiting the earliest step in angiogenesis and causing the chemoinvasion of endothelial cells (Sengupta et al., 2004). Additionally, CIG could also improve neurobehavioral deficits, decrease cerebral infarct size by reducing NO and inhibiting NF-B expression after focal cerebral ischemia (Li et al., 2005; Zhang et al., 2007). Resveratrol (3, 4 0 , 5-trihydroxy-trans-stilbene) is a major compound extracted from Polygonum cuspidatum. It had been confirmed that resveratrol could enhance myocardial angiogenesis both in vivo and in vitro. Moreover, pretreatment with resveratrol distinctly reduced the infarction zone at 24 hours after myocardial infarction and increased capillary density in a rat model (Kaga et al., 2005; Fukuda et al., 2006). Dong’s experiment confirmed that resveratrol administration after stroke was beneficial to reduce infarct volume and recover neurologic function in the delayed phase after stroke in MCAo and reperfusion injury models (Dong et al., 2008). Treatment of cerebral endothelial cells with resveratrol altered endothelial morphology, promoted cells proliferation, migration and tube formation. The mechanisms were related to the activation of PI3K/Akt and Mitogen-Activated

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Protein Kinase (MAPK)/ERK signaling pathways. Thus it showed eNOS played a pivotal role in this process (Simão et al., 2012). Naomaitong significantly down-regulated the expression of nNOS and iNOS in CIR of aged rats, and inhibited the neurotoxicity of NO (nNOS and iNOS source). At the same time it could increase the expression of eNOS and the neuro-protection of NO (eNOS source) in the early phase of cerebral ischemia. The mechanism of protecting the brain cells after focal CIR injury might be associated with activation of nuclear factor-kappa B (NFB), the 70 kilodalton heat shock proteins (HSP70) and NOSs (Gao et al., 2006).

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Matrix Metalloproteinase (MMP) MMP-2 and MMP-9 are the two types of matrix metalloproteinases (MMPs) which could degrade the protein in the extracellular matrix and be induced by CIR injury (Romanic et al., 1998; Jiang et al., 2001). A report demonstrated that tissue inhibitors of matrix metalloproteinase-1(TIMP-1) and -2 (TIMP-2) were endogenous inhibitors of MMP-2 and MMP-9, and possessed positive function to reduce the damage of CIR (Romanic and Madri, 1994). Naomaitong could reduce the degradation of the vascular basement membrane through MMP-2 and MMP-9 and improve the effect of TIMP-1 against the vascular basement membrane damage; thereby it contributed to protecting the microvascular basement membrane after CIR injury (Li et al., 2006). However, it is important for angiogenesis that activated endothelial cells can degrade the basement membrane and remodel the ECM around neovascular sites. Resveratrol had been found to directly up-regulate MMP-2 and MMP-9 production in cerebral endothelial cells, which contributed to angiogenesis (Simão et al., 2012). The above results indicated that it was very important that pharmacotherapy modulated MMPs to homeostasis. In additionally, research reported that Resveratrol markedly promoted the proliferation, migration, and adhesion of endothelial progenitor cells (EPCs) in vitro (Gu et al., 2006). Ginsenoside Rg1 induced EPCs proliferation and angiogenesis, and inhibited EPCs senescence. The mechanisms of Ginsenoside Rg1, which delayed the onset of cellular senescence and increased the capacity of EPCs, seemed to involve telomerase activity (Shi et al., 2011). These above studies have shown that Chinese Medicine’s active compounds and formulas can effectively promote angiogenesis and repair damaged tissue after stroke, which is related to modulating a variety of angiogenic factors and mobilizing endogenous EPCs. BMSCs Improve Angiogenesis Post-ischemic Stroke Stem cell-based therapy is a promising approach for stroke. From bench to bedside, Savitz and colleagues (2011) proposed the model of the Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) in 2008 which contributed to the pre-clinical results transforming to clinical trials. Some studies had revealed mechanisms of cells derived from bone marrow mediating angiogenesis after stroke in part.

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In 2005, Bang and colleagues (2005) described autologous mesenchymal stem cells (MSCs) appeared to be a feasible and safe therapy that might improve functional recovery in patients with severe cerebral infarcts. By transplanting BMSCs into the perilesional area in five patients bearing sequels of stroke, it seemed that BMSCs could be safely transplanted into the brain of patients with excellent tolerance and without complications (Suárez-Monteagudo et al., 2009). As multi-potency cells derived from the bone marrow stroma, BMSCs are recognized to be a candidate for neovascularization and tissues regeneration post-stroke. Though the defined mechanism of BMSCs treatment for stroke is still unknown, most studies indicated the therapeutic effect on stroke probably was relevant to BMSCs paracrine. For example, these cells might secrete trophic factors to promote synaptogenesis and neurogenesis (Pavlichenko et al., 2008; Onteniente and Polentes, 2011). However, Kelly and colleagues (2004) found that these transplanted human fetal NSCs would need several months to fully acquire terminal neurochemical phenotype; thus it is still to be demonstrated whether the improvement of neuro-function after stroke is attributed to direct differentiation of BMSCs in such a short time. In addition to the stimulation of synaptogenesis, neurogenesis and reduction of neuronal apoptosis post-stroke, BMSCs were also capable of promoting angiogenesis in ischemic zone (Chen et al., 2003a, 2004; Zhang et al., 2006; Pavlichenko et al., 2008). By intracranially injecting human MSCs into mice stroke model subjected to FeCl3 thrombosis, it was demonstrated that MSCs could reduce infarction zone partly by the improvement of angiogenesis (Mora-Lee et al., 2012). And intravenously injecting MSCs into MCAo rats, the study showed similar results which increased VEGF secretion, VEGFR2 expression and tube formation in the IBZ after stroke (Chen et al., 2003b). Therefore, it is very important to enhance angiogenesis for BMSCs transplantation after stroke, because formed new blood vessels could provide metabolism restoration and contribute to immature neuron migration, differentiation and survival for a longer time (Pavlichenko et al., 2008). A number of studies indicated ameliorating microenvironment in the ischemic zone was the most possible result of BMSCs engraftment. BMSCs could active astrocytes and microvascular endothelial cells etc. by releasing cytokines and trophic factors. And these molecules might reduce cell apoptosis and glial-scar formation, promote angiogenesis and neuroplasticity, and attenuate inflammation (Chen et al., 2003b; Bacigaluppi et al., 2009. BMSCs Mediate Angiogenic Factors Besides the role in angiogenesis, VEGF is now also recognized as a neurotrophic, neuroprotective and neuro-proliferative factor. Deng and colleagues (2010) found BMSCs could secrete VEGF and improve neurons survival and proliferation in the MCAo rat, whose effect could be counteracted by BMSCs transfection of VEGF RNAi lentivirus. Zacharek and colleagues (2007) reported BMSCs treatment could significantly increase Ang1 and its receptor Tie2 expression in IBZ, as well as conditional media from BMSCs co-culture with astrocytes or mouse brain endothelial cells (MBECs) could enhance

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respectively Ang1/Tie2 expression of astrocytes and MBECs, therefore, the enhancement of Ang1/Tie2 expression could facilitate MBECs to form capillary tube. Moreover, conditional serum derived from the co-culture of BMSCs and MBECs could also improve VEGFR2 expression of MBECs, and the tube formation was inhibited by using Flk1 inhibitor.

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BMSCs Mediate SDF-1/CXCR4 Axis Studies found stromal-derived factor-1 (SDF-1)/chemokine (CXC motif) receptor-4 (CXCR4) axis not only mediated the migration of engrafted BMSCs towards ischemic brain lesion in MCAo rat, but also promoted neovascularization (Salvucci et al., 2002; Wang et al., 2008). Endothelial cells from healthy and tumor tissues incubated with VEGF and β-FGF could improve the secretion of SDF-1 and tube formation, but the effect was offset by using a SDF-1/CXCR4 inhibitor in vitro (Salvucci et al., 2002). So as essential regulators of endothelial cell morphogenesis and angiogenesis, SDF-1 and CXCR4 play significant roles in ECM dependent endothelial tube formation. A previous study (Zacharek et al., 2007) had found BMSCs could release VEGF and have a beneficial effect on the activation of brain microvascular endothelial cells (BMECs) and astrocytes, thereby enhancing SDF-1/CXCR4 axis contributed to endothelial cells tube formation. Combination of Chinese Medicines and BMSCs Promotes Angiogenesis Post-ischemic Stroke Based on the previous results, the combination of Chinese medicines and BMSCs is a promising approach for the treatment of stroke (see Fig. 1). A study found that Astragaloside IV combined with BMSC could significantly promote a functional outcome and angiogenesis. The therapeutic effect of combination treatment was better than that of either the single treatment after CIR in rats and the mechanisms might be related to Astragaloside IV up-regulating SDF-1 and VEGF expression in the ischemic brain, promoting BMSC survival and migration (Wang et al., 2011b). NaomaiYihao (NMYH) capsule combined with BMSCs transplantation significantly improved CD31 expression and angiogenesis in focal cerebral ischemia of rats (Guo et al., 2009), and the authors further reported that the combination of NMYH capsule and VEGFtransfected BMSCs could promote angiogenesis in MCAo rats, which was relevant to the up-regulation of VEGF expression (Guo et al., 2012). In the study on the effect of Naomaitong combing with BMSCs against cerebral ischemic injure, the combination group could significantly enhance the numbers of CD34-positive cells in brain tissue (Li et al., 2009). As a Chinese herbal medicine mixture which was widely used to treat cardiovascular and cerebrovascular diseases in China, TXL cultured with BMSCs increased BMSCs tube formation in matrigel via the up-regulation of MMP-2 and VEGF expressions (Hu et al., 2011). BHD combined with MSCs transplantation repairs the injured blood vessels and lesion tissues possibly by up-regulating VEGF and Ki-67 expressions (Zhang et al., 2010).

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Figure 1. BMSCs combined with Chinese medicines enhances angiogenesis after ischemic stroke.

Conclusion Because BMSCs are easily isolated and do not obey the normal rules of allogenic rejection, the potential of BMSCs for treatment of ischemic stroke in allogenic transplantation has significant clinical worth. However, there are still crucial problems need to been solved, such as the engraft time window, the quantity of BMSCs transplantation and transplantation approaches, etc. Experimental evidence indicated that Chinese medicines could enhance angiogenesis by mediating angiogenic factors and activating cells signal pathways. However, it is still very necessary to choose suitable active components or formulas of Chinese medicines combined with BMSCs to further improve angiogenesis for treatment of ischemic stroke. On the other hand, some possible side effects must be considered when this strategy is applied. Because accelerating plaque angiogenesis can lead to the expansion and rupture of plaque, the potential risk of angiogenesis-borne disease existed such as formation and metastasis of tumor, aggravation of diabetic retinopathy and so on. Thus, we propose that a combination of BMSCs and Chinese medicines should mediate angiogenesis to homeostasis.

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Acknowledgments This study was supported by the Science and Technology Development Fund of Macao Special Administrative Region (FDCT: No. 089/2012/A3).

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Therapeutic angiogenesis after ischemic stroke: Chinese medicines, bone marrow stromal cells (BMSCs) and their combinational treatment.

Ischemic stroke is a clinical acute disease which causes neurological dysfunction and threatens a patient's life. Because the mechanism of pathology i...
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