**Author details**

of the most strongly expressed genes in DA ECs compared to aortic ECs, especially in fetal tissue [21]. Calpain-6 was recently implicated in tumor angiogenesis. Specifically, calpain-6 is suggested to play an important role in bone tumorigenesis and metastasis [91]. In the study, calpain-6 was found to be upregulated by ET-1, and to provide a protective effect against cell apoptosis and promote cell proliferation [91]. As mentioned earlier, ET-1 is increased in the DA to regulate its vasoconstriction [48–50]. Therefore, calpain-6 might be a newly identified

Studying EC heterogeneity aids our understanding of the physiology and pathophysiology of angiogenesis. It also has great potential to identify novel ways to regulate angiogenesis for treatment purposes. Comprehensive gene analysis using a microarray made it possible to reveal many genes that were previously functionally unidentified in tissue or disease. Molecular analyses using whole tissues hinder the data on specific cell types. ECs are the key cells responsible for primarily generating signaling pathways to modulate the functions or structure of a vessel. Vessels mainly consist of a medial layer (the majority of which is composed of SMCs), and a single layer of ECs. The separation of ECs would therefore be the first

This chapter focused on reviewing the current knowledge of DA ECs, since we believe that the DA could be utilized as a vessel model for studying the mechanisms of both neointimal formation and apoptosis in addition to embryonic vasculogenesis. DA-specific ECs are highly unique compared to aortic ECs in terms of their heterogeneity. DA ECs have a great number of specific genes related to ECM formation, inflammatory response, EMT or EndMT, and oxygen and retinoic acid response. DA ECs also have more genes that are conserved from embryogenesis compared to adjacent aortic ECs. In our previous study, Slac38a1, Capn6, and Lrat were found to be the most significantly expressed genes in DA ECs. Although much more research is required to validate the importance of these newly identified dominant genes in DA ECs, we expect that these findings will promote further studies on PDA, thera-

We would like to thank Dr. Hua Cai for supporting N.M. Liu's continuing research at the University of California, Los Angeles, as well as the fellowship support from the American Heart Association, Western States Affiliate Winter 2014 Predoctoral Fellowship (Award#14PRE20380184), and the American Association of Japanese University Women 2016. This work was also supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.M.), the Vehicle Racing Commemorative Foundation (S.M.), The Jikei University Graduate Research Fund (SM) and the Miyata Cardiology

gene in ET-1 signaling generated in DA ECs.

186 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

hurdle to overcome in order to acquire data on ECs.

peutic angiogenesis, and cancer treatment.

Research Promotion Foundation (S.M.).

**Acknowledgements**

**3. Conclusion**

Norika Mengchia Liu<sup>1</sup> and Susumu Minamisawa2 \*


## **References**


[27] Hsieh YT, Liu NM, Ohmori E, et al. (2014) Transcription profiles of the ductus arteriosus in Brown-Norway rats with irregular elastic fiber formation. *Circulation Journal: Official Journal of the Japanese Circulation Society* **78:** 1224–1233.

[12] Drake CJ. (2003) Embryonic and adult vasculogenesis. *Birth Defects Research. Part C,* 

[13] Dejana E, Taddei A, Randi AM. (2007) Foxs and Ets in the transcriptional regulation of endothelial cell differentiation and angiogenesis. *Biochimica et Biophysica Acta* **1775:**

[14] Rossig L, Urbich C, Bruhl T, et al. (2005) Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells. *Journal of* 

[15] Myers C, Charboneau A, Boudreau N. (2000) Homeobox B3 promotes capillary morpho-

[16] Gorski DH, Walsh K. (2000) The role of homeobox genes in vascular remodeling and

[17] Downes M, Koopman P. (2001) SOX18 and the transcriptional regulation of blood vessel

[18] Kuhnert F, Campagnolo L, Xiong JW, et al. (2005) Dosage-dependent requirement for mouse Vezf1 in vascular system development. *Developmental Biology* **283:** 140–156. [19] Gournay V. (2011) The ductus arteriosus: physiology, regulation, and functional and

[20] Weber SC, Gratopp A, Akanbi S, et al. (2011) Isolation and culture of fibroblasts, vascular smooth muscle, and endothelial cells from the fetal rat ductus arteriosus. *Pediatric* 

[21] Liu NM, Yokota T, Maekawa S, et al. (2013) Transcription profiles of endothelial cells in

[22] Bokenkamp R, van Brempt R, van Munsteren JC, et al. (2014) Dlx1 and Rgs5 in the ductus arteriosus: vessel-specific genes identified by transcriptional profiling of laser-cap-

[23] Mueller PP, Drynda A, Goltz D, Hoehn R, Hauser H, Peuster M. (2009) Common signatures for gene expression in postnatal patients with patent arterial ducts and stented

[24] Costa M, Barogi S, Socci ND, et al. (2006) Gene expression in ductus arteriosus and aorta:

[25] Jin MH, Yokoyama U, Sato Y, et al. (2011) DNA microarray profiling identified a new role of growth hormone in vascular remodeling of rat ductus arteriosus. *The Journal of* 

[26] Yokoyama U, Sato Y, Akaike T, et al. (2007) Maternal vitamin A alters gene profiles and structural maturation of the rat ductus arteriosus. *Physiological Genomics* **31:** 139–157.

comparison of birth and oxygen effects. *Physiological Genomics* **25:** 250–262.

ture microdissected endothelial and smooth muscle cells. *PLoS One* **9:** e86892.

genesis and angiogenesis. *The Journal of Cell Biology* **148:** 343–351.

development. *Trends in Cardiovascular Medicine* **11:** 318–324.

congenital anomalies. *Archives of Cardiovascular Diseases* **104:** 578–585.

the rat ductus arteriosus during a perinatal period. *PloS One* **8:** e73685.

*Embryo Today: Reviews* **69:** 73–82.

188 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

*Experimental Medicine* **201:** 1825–1835.

angiogenesis. *Circulation Research* **87:** 865–872.

arteries. *Cardiology in the Young* **19:** 352–359.

*Physiological Sciences: JPS* **61:** 167–179.

298–312.

*Research* **70:** 236–241.


[51] Brouard S, Otterbein LE, Anrather J, et al. (2000) Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. The *Journal of Experimental Medicine* **192:** 1015–1025.

[39] Li L, Zhang K, Cai XJ, Feng M, Zhang Y, Zhang M. (2011) Adiponectin upregulates prolyl-4-hydroxylase alpha1 expression in interleukin 6-stimulated human aortic smooth

[40] Chen MM, Lam A, Abraham JA, Schreiner GF, Joly AH. (2000) CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in

[41] Szeto CC, Lai KB, Chow KM, Szeto CY, Wong TY, Li PK. (2005) Differential effects of transforming growth factor-beta on the synthesis of connective tissue growth factor and vascular endothelial growth factor by peritoneal mesothelial cell. *Nephron. Experimental* 

[42] Lai KB, Sanderson JE, Yu CM. (2013) The regulatory effect of norepinephrine on connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF) expression in cultured cardiac fibroblasts. *International Journal of Cardiology* **163:**

[43] Clyman RI, Hardy P, Waleh N, et al. (1999) Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus. *The American Journal of Physiology*

[44] Baragatti B, Brizzi F, Ackerley C, Barogi S, Ballou LR, Coceani F. (2003) Cyclooxygenase-1 and cyclooxygenase-2 in the mouse ductus arteriosus: individual activity and functional coupling with nitric oxide synthase. *British Journal of Pharmacology* **139:** 1505–1515.

[45] Momma K, Toyono M. (1999) The role of nitric oxide in dilating the fetal ductus arterio-

[46] Richard C, Gao J, LaFleur B, et al. (2004) Patency of the preterm fetal ductus arteriosus is regulated by endothelial nitric oxide synthase and is independent of vasa vasorum in the mouse. *American Journal of Physiology. Regulatory, Integrative and Comparative Physiology*

[47] Takizawa T, Kihara T, Kamata A. (2001) Increased constriction of the ductus arteriosus with combined administration of indomethacin and L-NAME in fetal rats. *Biology of the* 

[48] Coceani F, Kelsey L, Seidlitz E. (1996) Carbon monoxide-induced relaxation of the ductus arteriosus in the lamb: evidence against the prime role of guanylyl cyclase. *British* 

[49] Coceani F, Kelsey L, Seidlitz E, Korzekwa K. (1996) Inhibition of the contraction of the ductus arteriosus to oxygen by 1-aminobenzotriazole, a mechanism-based inactivator of

[50] Coceani F, Kelsey L, Seidlitz E, et al. (1997) Carbon monoxide formation in the ductus arteriosus in the lamb: implications for the regulation of muscle tone. *British Journal of* 

cytochrome P450. *British Journal of Pharmacology* **117:** 1586–1592.

muscle cells by regulating ERK 1/2 and Sp1. *PLoS One* **6:** e22819.

190 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

*Nephrology* **99:** e95–e104.

183–189.

**276:** R913–921.

**287:** R652–660.

*Neonate* **80:** 64–67.

sus in rats. *Pediatric Research* **46:** 311–315.

*Journal of Pharmacology* **118:** 1689–1696.

*Pharmacology* **120:** 599–608.

heart fibrosis. *Journal of Molecular and Cellular Cardiology* **32:** 1805–1819.


[79] Ivey KN, Sutcliffe D, Richardson J, Clyman RI, Garcia JA, Srivastava D. (2008) Transcriptional regulation during development of the ductus arteriosus. *Circulation Research* **103:** 388–395.

[65] Gunaje JJ, Bahrami AJ, Schwartz SM, Daum G, Mahoney WM, Jr. (2011) PDGF-dependent regulation of regulator of G protein signaling-5 expression and vascular smooth muscle

[66] Levet S, Ouarne M, Ciais D, et al. (2015) BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus. *Proceedings of the National Academy of Sciences of the United* 

[67] Hajj H, Dagle JM. (2012) Genetics of patent ductus arteriosus susceptibility and treat-

[68] Ricard N, Ciais D, Levet S, et al. (2012) BMP9 and BMP10 are critical for postnatal retinal

[69] David L, Mallet C, Mazerbourg S, Feige JJ, Bailly S. (2007) Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in

[70] Loftin CD, Trivedi DB, Tiano HF, et al. (2001) Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. *Proceedings of the National Academy of Sciences of the United States of America* **98:** 1059–1064.

[71] Yokoyama U, Minamisawa S, Quan H, et al. (2006) Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus

[72] Akaike T, Jin MH, Yokoyama U, et al. (2009) T-type Ca2+ channels promote oxygenationinduced closure of the rat ductus arteriosus not only by vasoconstriction but also by

[73] Frey RS, Ushio-Fukai M, Malik AB. (2009) NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. *Antioxidants & Redox Signaling*

[74] Lee S, Paudel O, Jiang Y, Yang XR, Sham JS. (2015) CD38 mediates angiotensin II-induced intracellular Ca2+ release in rat pulmonary arterial smooth muscle cells. *American Journal* 

[75] Smith SM, Dickman ED, Power SC, Lancman J. (1998) Retinoids and their receptors in

[76] Wu GR, Jing S, Momma K, Nakanishi T. (2001) The effect of vitamin A on contraction of

[77] O'Byrne SM, Wongsiriroj N, Libien J, et al. (2005) Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT). *The Journal of Biological* 

[78] Bergwerff M, DeRuiter MC, Gittenberger-de Groot AC. (1999) Comparative anatomy and ontogeny of the ductus arteriosus, a vascular outsider. *Anatomy and Embryology* **200:** 559–571.

neointima formation. *The Journal of Biological Chemistry* **284:** 24025–24034.

arteriosus. *The Journal of Clinical Investigation* **116:** 3026–3034.

*of Respiratory Cell and Molecular Biology* **52:** 332–341.

vertebrate embryogenesis. *The Journal of Nutrition* **128:** 467S–470S.

the ductus arteriosus in fetal rat. *Pediatric Research* **49:** 747–754.

cell functionality. *American Journal of Physiology. Cell Physiology* **301:** C478–489.

*States of America* **112:** E3207–3215.

ment. *Seminars in Perinatology* **36:** 98–104.

192 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

vascular remodeling. *Blood* **119:** 6162–6171.

endothelial cells. *Blood* **109:** 1953–1961.

**11:** 791–810.

*Chemistry* **280:** 35647–35657.


## **Vascular Repair and Remodeling: A Review Vascular Repair and Remodeling: A Review**

Nicolás F. Renna, Rodrigo Garcia, Jesica Ramirez and Roberto M. Miatello Nicolás F. Renna, Rodrigo Garcia, Jesica Ramirez and Roberto M. Miatello

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67485

#### **Abstract**

Vascular remodeling is alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. In this review, physiopathology of vascular remodeling is discussed, and the impact of antihypertensive drug treatment on remodeling is described, emphasizing on human data, fundamentally as an independent predictor of cardiovascular risk in hypertensive patients. Then we discussed a vascular repair by endothelial progenitor cells (EPCs) that play important roles in the regeneration of the vascular endothelial cells (ECs). The normal arterial vessel wall is mostly composed of ECs, vascular smooth muscle cells (VSMCs), and macrophages. Endothelial impairment is a major contributor to atherosclerosis and restenosis after percutaneous coronary intervention (PCI). Reendothelialization can effectively inhibit VSMC migration and proliferation and decrease neointimal thickening.

**Keywords:** endothelial progenitor cells, fructose-fed hypertensive rats, metabolic syndrome, hypertension, oxidative stress, vascular remodeling

**1. Role of endothelial progenitor cells in vascular repair**

Vascular diseases, including atherosclerosis, media calcification, and microangiopathy, are prevalent in patients with diabetes mellitus and are considered to be primary causes of death and disability in these individuals [1]. Atherosclerosis occurs earlier in patients with diabetes, frequently with greater severity and a more diffuse distribution. Patients with diabetes have increased prevalence of vascular disease and, as a result, increased morbimortality from acute myocardial infarction. Diabetes and metabolic syndrome (MS) are associated with vascular function abnormalities and ensuing morphological changes associated with vascular remodeling and atherosclerosis [2, 3].

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. 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, © 2017 The Author(s). Licensee InTech. 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, provided the original work is properly cited.

The arterial vessel wall is mostly composed of endothelial cells (ECs), vascular smooth muscle cells (VSMCs), adventitial connective tissue and macrophages. Endothelial impairment is believed to be a major contributor to atherosclerosis or restenosis after percutaneous coronary intervention (PCI). Reendothelialization with ECs can effectively inhibit VSMC migration and proliferation and decrease neointimal thickening. It is for this reason that we studied a mechanism to achieve a rapid reendothelialization, through, for example, autologous translators of endothelial progenitor cells (EPC), mature or immature, as a fundamental hypothesis in the prevention of these two pathologies: atherosclerosis and restenosis, which derive in the same clinical entity: acute coronary syndrome.

EPCs are divided into different evolutionary stages from mother cells to mature ECs. Both early and late EPCs can repair blood vessels, but late EPCs that have a strong proliferation capacity are more involved in the formation of new vessels or angiogenesis. By measuring EPC in patients by flow cytometry in patients by flow cytometry, we found that in patients with atherosclerosis are decreased compared to control subjects without atherosclerosis [4–6]. Several studies show that EPCs can be recruited to sites of endothelial injury then mature in site, changing cluster of differentiation (CD), and playing a major role in reendothelialization [7–9].

Atherosclerosis is an inflammatory disease with leukocyte infiltration, accumulation of smooth muscle cells, and formation of neointima. Damage of the endothelial monolayer triggers the development of thrombosis with consequent occlusion versus arterial subocclusion. Recent studies demonstrated the recruitment and incorporation of EPC into atherosclerotic lesions and therefore provided evidence supporting the role of vascular cells in the pathophysiology of atherosclerosis. Moreover, there is evidence that EPC are capable of regenerating cells, vascular grafts, and native vessels [10, 11].

The EPCs can mediate vascular repair and attenuate atherosclerosis progression even in the continued presence of vascular injury. Although the mechanisms involved are still not clear, EPCs seem to contribute to the restoration of the endothelial monolayer [12]. In addition to bone marrow, spleen-derived EPCs also have the capacity to repair damaged endothelium [13]. EPCs derived from spleen homogenates also enhanced reendothelialization and reduce neointima formation after induction of endothelial cell damage using the carotid artery model [14].

Other models have also been used, such as the balloon injury model, mobilization of circulating EPCs, and accelerated repair of the nude endothelium [15]. In addition, autologous EPCs that overexpress endothelial nitric oxide synthase (eNOS) ameliorates endothelial integrity when transplanted into mice after carotid artery balloon injury. Increased NO bioavailability significantly strengthens the vasoprotective properties of the reconstituted endothelium, leading to inhibition of neointimal hyperplasia [16].

Transfer of progenitor cells is not always beneficial. ApoE KO mice receiving mononuclear bone marrow cells, following induced hind limb ischemia, showed increased neovascularization, accelerated atherosclerotic plaque formation, and lesion size compared to control groups [17]. In an alternate study, because of proinflammatory properties of these cells, as reduction in IL-10 levels in the atherosclerotic aortas was observed accelerated atherosclerosis along with reduced plaque stability [18]. Similarly, even though implantation of an arteriovenous anti-CD34-ePTFE graft in pigs, it also stimulated intimal hyperplasia [19, 20]. Besides obvious differences in various experimental models, it is difficult to reconcile these findings and it seems that excessive mobilization of progenitor cells may lead to restenosis, but its absence may impair reendothelialization [21]. It is important to mention term EPC is loosely used to describe a vastly heterogenic cell population that is consisted of different progenitors. Recent studies have highlighted the impact of cell isolation protocols on the functional capacity, that is, different phenotypes.
