*5.1.1 Therapeutic potential of extracellular vesicles*

According to results from studies from the last 5 to 10 years, EVs could play an important role in different cardiac regenerative therapies and could also be used as therapeutic targets and vectors in cardiovascular medicine.

Platelet-derived vesicles induce vascular endothelial growth factor (VEGF) dependent angiogenesis and stimulate postischemic revascularization after chronic ischemia [93]. Also, plasma-derived exosomes activate Toll-like receptor 4 on cardiomyocytes and thus protect the myocardium from ischemia-reperfusion injury [94]. MSCs-derived EVs could be an alternative to stem cell transplantation after myocardial ischemia by transfer of specific miRNAs through embryonic stem cell EVs [95].

Different cardiovascular medications can influence the level of circulating MVs. Antiplatelet agents (ticlopidine and abciximab) inhibit platelet activation and also the release of platelet-derived MVs [96–98]. Antihypertensive agents (such as angiotensin II receptor inhibitors, beta blockers, and calcium channel blockers) lower the circulating levels of platelet- and monocyte-derived MVs [99]. The effects of statin treatment on circulating MVs of platelet and endothelial origin are still unclear [100, 101].

Statins and antihypertensive medication are able to modify the properties of in vivo-generated endothelial MVs and their effect on the expression of endothelial adhesion molecules, inhibiting the adhesion of monocytes to ECs and improving endothelial function [102].

In other words, MVs are now regarded as novel therapeutic targets to monitor the therapeutic response to treatments in diabetic macrovascular complications. The beneficial effects of several drugs, such as statins, antiplatelet agents, antioxidants, angiotensin II receptor blockers, and calcium-channel blockers, have been reported to be partially due to their effects on reduction of both MV numbers and/or procoagulant factors [103]. Moreover, the cardiovascular benefits of antihyperglycemic drugs used to treat type 2 diabetic patients, such as, glibenclamide [104], acarbose [105], miglitol [106], and gliclazide [107], might be at least partially attributed to the anti-atherothrombotic effects of medication, through the decrease of procoagulant MV levels and platelet-activating factors. Pioglitazone treatment reduced the level of circulating endothelial-derived-MVs and increased the level of EPCs and the endothelial-derived MVs/EPCs ratio, improving the imbalance between endothelial damage and repair capacity [108]. Moreover, in our studies on atherosclerotic animal model and patients with hypertension and dyslipidemia, we showed that administration of irbesartan, an AT1 receptor antagonist, decreases the levels of circulating MVs, and also of specific MVs (endothelial-, platelet-, and leukocyte-derived MVs), and increases EPC levels, preventing the appearance of vascular endothelial dysfunction [78]. The mechanisms underlying this response include the reduction/increase of a number of specific membrane receptors exposed by MPs (TF, P-selectin, E-selectin, PSGL-1, Rantes), respectively, by EPCs (β2-Integrins and α4β1-integrin), the augmentation of endothelium-mediated

**121**

*Part One: Extracellular Vesicles as Valuable Players in Diabetic Cardiovascular Diseases*

therapeutic vectors in CVDs are few and are only on animal models.

vasodilation and the reduction of protein expression of VEGF/stromal cell-derived

In addition to their role as drug targets, EVs are an attractive drug delivery vehicle. The use of EVs as therapeutic vectors could be done through bioengineering, either by modifying the cytosolic content of the vesicles which could be transferred to the target cells in order to influence cell metabolism, or by loading of EVs with molecules to be delivered to target cells. Studies regarding the use of EVs as

EVs present some individual features, which make them promising therapeutic tools, and emphasize EV-based therapies as a promising alternative to cell therapy in cardiovascular medicine. Using EV-based therapeutics avoids biological issues associated with cell-based strategies, such as stress-induced necrosis or aberrant

Thus, EVs have a particular stability over time conferred by their membranous structures that make them real "off-the-shelf" tools allowing careful maintenance of stability, integrity, and biological activity during their manufacture, storage, and subsequent administration [111]. Moreover, EV lipid bilayer coat protects their bioactive cargo from degradation when they circulate from one cell to another. The small size of EVs, compared to whole cells, also offers therapeutic benefits, such as decreased macrophage phagocytosis and vascular occlusion, and easier injection [110]. Additionally, EVs have innate biocompatibility, low toxicity and immunogenicity, and selective uptake that make them an excellent delivery vehicle

With all these features, at this time, EVs represent attractive nanocarriers for

In order to enhance the EVs' therapeutic capabilities and applicability, methodologies have been developed for loading them with non-native cargo and also, several targeting strategies for systemically delivery. The two main categories of current strategies are: (i) approaches focused on cellular modification and

The most common therapeutic approaches that have used EVs are: (i) to deliver small RNAs attempting to reverse pathological miRNA-based communication with anti-miRNA oligonucleotides or (ii) to stimulate protective communication with synthetic miRNA mimics [114, 115]. More specific delivery of anti-miRNAs or miRNA mimics to target cells is realized by engineering vesicles with cell-selective surface proteins [116], which should reduce off-target effects. The ability to load EVs with miRNAs suggests the possibility of using EVs to deliver miRNA-based therapeutics in CVDs. The field of miRNA-based therapies is advancing rapidly, and research focused on circulating EVs and their miRNA content has revealed

However, not many studies have focused their objective in the use of EVs as therapeutic tools against CVDs. In this regard, in a mouse model of type 1 diabetes, it was shown that MSCs-derived EVs delayed the onset of type 1 diabetes through modulation of IL-1β-mediated pancreatic B-cell damage [117]. Moreover, EVs secreted by induced pluripotent stem cells deliver cardioprotective miR-21 and miR-210, preventing cardiomyocyte apoptosis in the ischemic

More information exists in the literature concerning the individual subsets of EVs: exosomes and MVs as therapeutic targets and biomedical tools. For instance, it was reported that cardiomyocytes exert an anti-angiogenic function in type 2 diabetic rats through exosomal transfer of miR-320 into ECs [119]. Further research showed that exosomes derived from cardiomyocytes overexpressing

drugs as well as therapeutic small molecules, nucleic acids, and proteins.

(ii) methods focused on direct EV alteration [113].

diverse and important roles [112].

myocardium [118].

*DOI: http://dx.doi.org/10.5772/intechopen.85225*

factor-1α (SDF-1α) [109].

differentiation [110].

for therapeutics [112].

*Part One: Extracellular Vesicles as Valuable Players in Diabetic Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.85225*

vasodilation and the reduction of protein expression of VEGF/stromal cell-derived factor-1α (SDF-1α) [109].

In addition to their role as drug targets, EVs are an attractive drug delivery vehicle. The use of EVs as therapeutic vectors could be done through bioengineering, either by modifying the cytosolic content of the vesicles which could be transferred to the target cells in order to influence cell metabolism, or by loading of EVs with molecules to be delivered to target cells. Studies regarding the use of EVs as therapeutic vectors in CVDs are few and are only on animal models.

EVs present some individual features, which make them promising therapeutic tools, and emphasize EV-based therapies as a promising alternative to cell therapy in cardiovascular medicine. Using EV-based therapeutics avoids biological issues associated with cell-based strategies, such as stress-induced necrosis or aberrant differentiation [110].

Thus, EVs have a particular stability over time conferred by their membranous structures that make them real "off-the-shelf" tools allowing careful maintenance of stability, integrity, and biological activity during their manufacture, storage, and subsequent administration [111]. Moreover, EV lipid bilayer coat protects their bioactive cargo from degradation when they circulate from one cell to another. The small size of EVs, compared to whole cells, also offers therapeutic benefits, such as decreased macrophage phagocytosis and vascular occlusion, and easier injection [110]. Additionally, EVs have innate biocompatibility, low toxicity and immunogenicity, and selective uptake that make them an excellent delivery vehicle for therapeutics [112].

With all these features, at this time, EVs represent attractive nanocarriers for drugs as well as therapeutic small molecules, nucleic acids, and proteins.

In order to enhance the EVs' therapeutic capabilities and applicability, methodologies have been developed for loading them with non-native cargo and also, several targeting strategies for systemically delivery. The two main categories of current strategies are: (i) approaches focused on cellular modification and (ii) methods focused on direct EV alteration [113].

The most common therapeutic approaches that have used EVs are: (i) to deliver small RNAs attempting to reverse pathological miRNA-based communication with anti-miRNA oligonucleotides or (ii) to stimulate protective communication with synthetic miRNA mimics [114, 115]. More specific delivery of anti-miRNAs or miRNA mimics to target cells is realized by engineering vesicles with cell-selective surface proteins [116], which should reduce off-target effects. The ability to load EVs with miRNAs suggests the possibility of using EVs to deliver miRNA-based therapeutics in CVDs. The field of miRNA-based therapies is advancing rapidly, and research focused on circulating EVs and their miRNA content has revealed diverse and important roles [112].

However, not many studies have focused their objective in the use of EVs as therapeutic tools against CVDs. In this regard, in a mouse model of type 1 diabetes, it was shown that MSCs-derived EVs delayed the onset of type 1 diabetes through modulation of IL-1β-mediated pancreatic B-cell damage [117]. Moreover, EVs secreted by induced pluripotent stem cells deliver cardioprotective miR-21 and miR-210, preventing cardiomyocyte apoptosis in the ischemic myocardium [118].

More information exists in the literature concerning the individual subsets of EVs: exosomes and MVs as therapeutic targets and biomedical tools. For instance, it was reported that cardiomyocytes exert an anti-angiogenic function in type 2 diabetic rats through exosomal transfer of miR-320 into ECs [119]. Further research showed that exosomes derived from cardiomyocytes overexpressing

*Extracellular Vesicles and Their Importance in Human Health*

*5.1.1 Therapeutic potential of extracellular vesicles*

insight into vascular complications and vascular risk in diabetes.

therapeutic targets and vectors in cardiovascular medicine.

(KLF5)-overexpressing VSMCs and it is considered as a potent regulator of endothelium barrier function through regulating endothelial targeting tight junction protein expression. In murine model of atherosclerosis, VSMCs-derived exosomes mediated the transfer of miR-155 from VSMCs to ECs, which led to an increased endothelial permeability and enhanced atherosclerotic progression [92]. These data suggest the possible role of UEVs in kidney remodeling, which can bring the new

According to results from studies from the last 5 to 10 years, EVs could play an important role in different cardiac regenerative therapies and could also be used as

Platelet-derived vesicles induce vascular endothelial growth factor (VEGF) dependent angiogenesis and stimulate postischemic revascularization after chronic ischemia [93]. Also, plasma-derived exosomes activate Toll-like receptor 4 on cardiomyocytes and thus protect the myocardium from ischemia-reperfusion injury [94]. MSCs-derived EVs could be an alternative to stem cell transplantation after myocardial ischemia by transfer of specific miRNAs through embryonic stem cell

Different cardiovascular medications can influence the level of circulating MVs.

Statins and antihypertensive medication are able to modify the properties of in vivo-generated endothelial MVs and their effect on the expression of endothelial adhesion molecules, inhibiting the adhesion of monocytes to ECs and improving

In other words, MVs are now regarded as novel therapeutic targets to monitor the therapeutic response to treatments in diabetic macrovascular complications. The beneficial effects of several drugs, such as statins, antiplatelet agents, antioxidants, angiotensin II receptor blockers, and calcium-channel blockers, have been reported to be partially due to their effects on reduction of both MV numbers and/or procoagulant factors [103]. Moreover, the cardiovascular benefits of antihyperglycemic drugs used to treat type 2 diabetic patients, such as, glibenclamide [104], acarbose [105], miglitol [106], and gliclazide [107], might be at least partially attributed to the anti-atherothrombotic effects of medication, through the decrease of procoagulant MV levels and platelet-activating factors. Pioglitazone treatment reduced the level of circulating endothelial-derived-MVs and increased the level of EPCs and the endothelial-derived MVs/EPCs ratio, improving the imbalance between endothelial damage and repair capacity [108]. Moreover, in our studies on atherosclerotic animal model and patients with hypertension and dyslipidemia, we showed that administration of irbesartan, an AT1 receptor antagonist, decreases the levels of circulating MVs, and also of specific MVs (endothelial-, platelet-, and leukocyte-derived MVs), and increases EPC levels, preventing the appearance of vascular endothelial dysfunction [78]. The mechanisms underlying this response include the reduction/increase of a number of specific membrane receptors

exposed by MPs (TF, P-selectin, E-selectin, PSGL-1, Rantes), respectively, by EPCs (β2-Integrins and α4β1-integrin), the augmentation of endothelium-mediated

Antiplatelet agents (ticlopidine and abciximab) inhibit platelet activation and also the release of platelet-derived MVs [96–98]. Antihypertensive agents (such as angiotensin II receptor inhibitors, beta blockers, and calcium channel blockers) lower the circulating levels of platelet- and monocyte-derived MVs [99]. The effects of statin treatment on circulating MVs of platelet and endothelial origin are still

**120**

EVs [95].

unclear [100, 101].

endothelial function [102].

heat shock protein 20 (Hsp20) protect against in vitro high glucose-triggered cell death as well as in vivo diabetes mellitus-induced cardiac adverse remodeling, suggesting that Hsp20-engineered exosomes might be a novel promising therapy [120]. Exosomes from human fibrocytes stimulated with platelet-derived growth factor-BB for 7 days and transforming growth factor-β for the following 3 days displayed both, in vitro and in vivo, wound healing properties in diabetic *db/db* mice [121]. Although it has been shown that this pharmacological treatment of human fibrocytes increased expressions of miR-126, miR-130a, miR-132, miR124a, miR-125b, and miR-21 into exosomes, the exact mechanism implicated in these effects is still unknown. In addition, administration of mouse brain endothelial cell-derived exosomes, loaded with miR-146a by chemical transfection method, into the brain's ventricle attenuates dementia-like pathology in diabetic *db/db* mice [122].

Several experimental data and preclinical models have demonstrated the excellent potential of stem cell-derived exosomes to be used as therapeutic tools in CVDs [111]. Thus, exosomes enriched with miR-22 secreted by MSCs following ischemic preconditioning was reported to have a significant benefit in cardiac recovery after myocardial infarction, by targeting the methyl CpG binding protein 2 [123]. Exosomes derived from human MSCs, carrying miR-21-5p, mediates effects on cardiac contractility and calcium handling, likely via PI3K signaling, opening new research ways in optimizing future stem cell-based cardiotherapies [124]. Furthermore, it was shown that exosomes secreted by human cardiosphere-derived cells enriched in miR146a inhibited apoptosis and promoted proliferation of cardiomyocytes, improving in this way angiogenesis. In another study, it has been showed that in cardiomyocytes cultured in a hypoxic environment, GATA-4 overexpressing MSCs-derived exosomes contribute to increased cardiomyocyte survival, reduced cardiomyocyte apoptosis, and preserved mitochondrial membrane potential [125]. Importantly, the use of exosomes isolated from MSCs for the reduction of inflammatory state during type 1 diabetes mellitus is mentioned into an Egyptian clinical trial (phase II-III, NCT02138331) [126].

In addition, it has been demonstrated that abnormal miRNA expression in MVs is involved in neoangiogenesis: (i) diminished expression of miRNA-200b reduces VEGF levels [127] and (ii) augmented expression of miR-29b regulates certain apoptotic genes and increases VEGF levels [128]. These data suggested that acting on these miRNA levels in MVs may control cell proliferation in diabetic retinopathy. Likewise, MVs cargo with miR-126 play an important role in angiogenesis and vascular integrity [129], while administration of the miR-126-enriched MVs to ApoE−/− mice could reduce the development of aortic plaques of atherosclerosis [130]. Importantly, it has been shown that MVs derived from EPCs, carrying specific miRNAs, activate angiogenesis through phosphatidylinositol 3 kinase/protein kinase B signaling pathway [129]. MVs derived from human acute monocytic leukemia cell line (THP-1 cells) treated by inflammatory factors contain miR-150 which may be involved in EC migration [226]. In a recent study, we showed that MVs of healthy origins promote EPC proliferation, adhesion, and migration, supporting reestablishment of EPC ability to incorporate in damaged endothelium and working in concert with existing ECs to form blood vessels [131]. These beneficial effects of MVs on late EPC dysfunctionality in atherosclerosis could be explained by the ability of MVs to transfer specific miRNA (miR-10a, miR21, miR-126, miR-146a, and miR-223) into recipient cells and by insulin-like growth factor- 1 expression activation [228].

Data summary concerning exosome and MV charge and their therapeutic effects are presented in the **Table 1**.

**123**

*cell line.*

**Table 1.**

miR-10a, miR21, miR-126, miR-146a, miR-223

*Part One: Extracellular Vesicles as Valuable Players in Diabetic Cardiovascular Diseases*

cells

Human fibrocytes Dermal fibroblasts,

miR-22 hMSCs Cardiomyocytes Enhances cardiac

miR-19a hMSCs Cardiomyocytes Restores cardiac

Cardiac endothelial

keratinocytes

iPSCs Cardiomyocytes Rescue ischemic

cardiomyocytes and iPSCs-derived fibroblasts

**MV charge MV source Recipient Therapeutic effects Reference**

<sup>−</sup> mice

ApoE<sup>−</sup>/

miR-150 THP-1 cells hMECs Modulates endothelial

*iPSCs, induced pluripotent stem cells; hMSCs, human mesenchymal stem cells; ECs, endothelial cells; EPCs, endothelial progenitor cells; hMECs, human microvascular endothelial cells; and THP-1 cells, human acute monocytic leukemia* 

mRNAs EPCs hMECs Activates

*Exosome and MV charge components and their therapeutic effects in diabetes and CVDs.*

**Exosome source Recipient Therapeutic effects Reference**

Endothelial cells Improves cardiac

Brain's ventricles Attenuates dementia-

Decreases

diabetes

function and angiogenesis in diabetes

Accelerate diabetic wound healing

like pathology in diabetes

cardiomyocytes

contractile function and reduces infarct

Increases engineered cardiac tissue contractility via PI3K

angiogenesis through phosphatidylinositol 3 kinase/protein kinase B signaling pathway

cell migration

proliferation, adhesion and migration in atherosclerosis

Late EPCs Promote EPC

function

size

signaling

Reduces the development of aortic plaques of atherosclerosis

angiogenesis in type 2

[119]

[120]

[121]

[122]

[118]

[123]

[125]

[124]

[130]

[129]

[129]

[131]

*DOI: http://dx.doi.org/10.5772/intechopen.85225*

cardiomyocytes

cardiomyocytes

endothelial cell

miR-21-5p hMSCs iPSCs-derived

miR-126 ECs Vascular cells from

Plasma from healthy hamsters

**Exosome charge**

miR-126, miR-130a, miR-132, miR124a, miR-125b, miR-21

miR-21, miR-210

miR-320 Rat

Hsp20 Mouse

miR-146a Mouse brain


*Part One: Extracellular Vesicles as Valuable Players in Diabetic Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.85225*

*iPSCs, induced pluripotent stem cells; hMSCs, human mesenchymal stem cells; ECs, endothelial cells; EPCs, endothelial progenitor cells; hMECs, human microvascular endothelial cells; and THP-1 cells, human acute monocytic leukemia cell line.*

#### **Table 1.**

*Extracellular Vesicles and Their Importance in Human Health*

*db/db* mice [122].

trial (phase II-III, NCT02138331) [126].

heat shock protein 20 (Hsp20) protect against in vitro high glucose-triggered cell death as well as in vivo diabetes mellitus-induced cardiac adverse remodeling, suggesting that Hsp20-engineered exosomes might be a novel promising therapy [120]. Exosomes from human fibrocytes stimulated with platelet-derived growth factor-BB for 7 days and transforming growth factor-β for the following 3 days displayed both, in vitro and in vivo, wound healing properties in diabetic *db/db* mice [121]. Although it has been shown that this pharmacological treatment of human fibrocytes increased expressions of miR-126, miR-130a, miR-132, miR124a, miR-125b, and miR-21 into exosomes, the exact mechanism implicated in these effects is still unknown. In addition, administration of mouse brain endothelial cell-derived exosomes, loaded with miR-146a by chemical transfection method, into the brain's ventricle attenuates dementia-like pathology in diabetic

Several experimental data and preclinical models have demonstrated the excellent potential of stem cell-derived exosomes to be used as therapeutic tools in CVDs [111]. Thus, exosomes enriched with miR-22 secreted by MSCs following ischemic preconditioning was reported to have a significant benefit in cardiac recovery after myocardial infarction, by targeting the methyl CpG binding protein 2 [123]. Exosomes derived from human MSCs, carrying miR-21-5p, mediates effects on cardiac contractility and calcium handling, likely via PI3K signaling, opening new research ways in optimizing future stem cell-based cardiotherapies [124]. Furthermore, it was shown that exosomes secreted by human cardiosphere-derived cells enriched in miR146a inhibited apoptosis and promoted proliferation of cardiomyocytes, improving in this way angiogenesis. In another study, it has been showed that in cardiomyocytes cultured in a hypoxic environment, GATA-4 overexpressing MSCs-derived exosomes contribute to increased cardiomyocyte survival, reduced cardiomyocyte apoptosis, and preserved mitochondrial membrane potential [125]. Importantly, the use of exosomes isolated from MSCs for the reduction of inflammatory state during type 1 diabetes mellitus is mentioned into an Egyptian clinical

In addition, it has been demonstrated that abnormal miRNA expression in MVs is involved in neoangiogenesis: (i) diminished expression of miRNA-200b reduces VEGF levels [127] and (ii) augmented expression of miR-29b regulates certain apoptotic genes and increases VEGF levels [128]. These data suggested that acting on these miRNA levels in MVs may control cell proliferation in diabetic retinopathy. Likewise, MVs cargo with miR-126 play an important role in angiogenesis and vascular integrity [129], while administration of the miR-126-enriched MVs to ApoE−/− mice could reduce the development of aortic plaques of atherosclerosis [130]. Importantly, it has been shown that MVs derived from EPCs, carrying specific miRNAs, activate angiogenesis through phosphatidylinositol 3 kinase/protein kinase B signaling pathway [129]. MVs derived from human acute monocytic leukemia cell line (THP-1 cells) treated by inflammatory factors contain miR-150 which may be involved in EC migration [226]. In a recent study, we showed that MVs of healthy origins promote EPC proliferation, adhesion, and migration, supporting reestablishment of EPC ability to incorporate in damaged endothelium and working in concert with existing ECs to form blood vessels [131]. These beneficial effects of MVs on late EPC dysfunctionality in atherosclerosis could be explained by the ability of MVs to transfer specific miRNA (miR-10a, miR21, miR-126, miR-146a, and miR-223) into recipient cells and by insulin-like growth factor- 1 expression

Data summary concerning exosome and MV charge and their therapeutic effects

**122**

activation [228].

are presented in the **Table 1**.

*Exosome and MV charge components and their therapeutic effects in diabetes and CVDs.*

## **6. Progress and challenges in extracellular vesicle field**

Although research into EV field is gaining ground, some challenges need to be overcome before using them in the clinic, such as: (i) optimization of EV isolation procedures, especially the time of protocols, decrease of amount of samples, and the selective isolation of distinct EV subtypes; (ii) the large-scale production in good manufacturing conditions; and (iii) increase of the specificity of engineered EVs vis-à-vis target cells to avoid the possible side effects [126].

Additionally, much still remains to be revealed regarding the role of EVs in cell-cell communication both in health and diabetic cardiovascular disorders. Specifically, understanding the effects of the chronic inflammatory environment in diabetes on the packaging and release of endothelial-EVs and their following interactions with cardiomyocytes could be useful [112]. Advancing the knowledge regarding the cellular source and destination of EVs in CVDs will allow exploration of the specific cellular interactions, while understanding EV organ-tropism will help to target specific tissues, improving the efficiency of miRNA-based therapies.

Even so, with many problems remaining to be resolved, as we mentioned above, prior EV-based therapeutics might be clinically used to treat CVDs. Anywise, the many studies underline their potential as successful therapeutic targets in combatting the heavy millstone of metabolic disease [112].

## **7. Conclusions**

Overall, our chapter strongly suggests that EVs may function as significant regulators of both physiological and pathological conditions and demonstrates their universal role in the relationship between diabetes and cardiovascular disease. Their unique properties as biological vectors modulating diabetic cardiovascular diseases, including atherosclerosis, coronary artery disease, and peripheral arterial disease, are also highlighted.

Undoubtedly, elucidation of terminology, biogenesis, biological content, and function of EVs contributes to better understanding of the complexity of their role in influencing the different processes affected in diabetic cardiovascular diseases. Consequently, we envisage that for EVs used as clinical biomarkers, therapeutic targets, and biomedical tools in diabetes and associated complications, there is a need for developing a molecular system of EVs based on their lipidomic, metabolomic, and miRnomic signature. Once these issues are clarified, preventative and therapeutic strategies can be implemented and further developed.

Despite the fact that existing literature discussed in this chapter describes the EV importance in diabetic cardiovascular diseases, it also leaves some significant questions unanswered. Thus, it becomes increasingly complicated to establish an EV structure either beneficial or harmful, to clarify their role either good or bad, in both health and disease. Incontestably, more research evaluating such properties is necessary to establish EVs' value as clinical biomarkers, therapeutic targets, and biomedical tools based on concrete scientific results for diabetic cardiovascular disease treatment.

### **Acknowledgements**

The authors are grateful to the work supported by grants of the Romanian National Authority for Scientific Research, CNCS-UEFISCDI, project no. PN-III-P1-1.2-PCCDI-2017-0527, project no. PN-III-P1-1.2-PCCDI-2017-0797, and by the Romanian Academy.

**125**

*Part One: Extracellular Vesicles as Valuable Players in Diabetic Cardiovascular Diseases*

The authors declare that the research was conducted in the absence of any either commercial or financial relationships that could be construed as a potential conflict

, Alexandru Filippi3

and Adriana Georgescu3

3 Pathophysiology and Pharmacology Department, Institute of Cellular Biology and

Pathology 'Nicolae Simionescu' of Romanian Academy, Bucharest, Romania

4 Cardiology Department, University and Emergency Hospital, Bucharest,

5 Department of Functional Sciences, 'Victor Babes' University of Medicine and

6 'Pius Brinzeu' Clinical Emergency County Hospital, OncoGen-Center for Gene

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and Cellular Therapies in the Treatment of Cancer, Timisoara, Romania

7 Department of Medical Physics, M. Smoluchowski Institute of Physics,

\*Address all correspondence to: adriana.georgescu@icbp.ro

, Stefania Lucia Magda2,4,

\*

, Octavian Costin Ioghen1,2,

, Virgil Paunescu5,6,

*DOI: http://dx.doi.org/10.5772/intechopen.85225*

Mihaela Gherghiceanu1,2, Nicoleta Alexandru3

Dragos Vinereanu2,4, Ewa Stepien7

Pharmacy, Timisoara, Romania

Jagiellonian University, Kraków, Poland

provided the original work is properly cited.

, Miruna Nemecz<sup>3</sup>

Laura Cristina Ceafalan1,2, Florina Bojin5,6, Gabriela Tanko3

2 Carol Davila University of Medicine, Bucharest, Romania

1 Victor Babeș National Institute of Pathology, Bucharest, Romania

**Conflict of interest**

of interest.

**Author details**

Alina Constantin3

Romania

*Part One: Extracellular Vesicles as Valuable Players in Diabetic Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.85225*
