arthyperАртериальная гипертензия"Arterial’naya Gipertenziya" ("Arterial Hypertension")1607-419X2411-8524Antihypertensive League10.18705/1607-419X-2017-23-5-447-456arthyper-687Research ArticleОБЗОРREVIEWМОРФОФУНКЦИОНАЛЬНЫЕ ИЗМЕНЕНИЯ ЭНДОТЕЛИЯ В ПАТОГЕНЕЗЕ ГИПЕРТОНИЧЕСКОЙ БОЛЕЗНИMORPHOFUNCTIONAL ALTERATIONS IN ENDOTHELIUM IN THE PATHOGENESIS OF ESSENTIAL HYPERTENSIONСысоевК. А.SysoevK. A.

Сысоев Кирилл Александрович — лаборатория середечнососудистой и лимфатической систем Института физиологии им. И. П. Павлова РАН; научный сотрудник НИО ишемической болезни сердца ФГБУ «НМИЦ им. В. А. Алмазова» Минздрава России.

наб. Макарова, д. 6, Санкт-Петербург, 199034.

Kirill A. Sysoev, Pavlov Institute of Physiology of the Russian Academy of Sciences; Researcher, Research Department of Coronary Heart Disease, Almazov National Medical Research Centre.

6 Makarov embankment, St Petersburg, 199034.

sysoev@infran.ruФедеральное государственное бюджетное учреждение  «Национальный медицинский исследовательский  центр имени В. А. Алмазова» Министерства здравоохранения  Российской Федерации;  Федеральное государственное бюджетное учреждение  науки «Институт физиологии имени И. П. Павлова»  Российской академии наук.РоссияAlmazov National Medical Research Centre; Pavlov Institute of PhysiologyRussian Federation201702112017235447456Copyright © Сысоев К.А., 20172017Сысоев К.А.Sysoev K.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://htn.almazovcentre.ru/jour/article/view/687

Эндотелий представляет собой многоуровневую клеточную структуру, пронизывающую все органы и системы организма. Гипертоническая болезнь (ГБ) является заболеванием, в основе патогенеза которого лежит нарушение регуляции тонуса магистральных артерий. Патогенетические основы ГБ, несмотря на интенсивные усилия, остаются неясными. Бесспорна неблагоприятная роль эмоционального стресса, гиподинамии, ожирения и нарушений водно-солевого обмена. Вместе с тем точные механизмы и предикторы развития артериальной гипертензии (АГ) в настоящее время не определены. Это препятствует профилактике и выявлению эссенциальной гипертензии на ранней стадии. Изучение функции эндотелия как мишени и предрасполагающего фона развития ГБ является задачей, имеющей как исследовательское, так и прикладное, клиническое значение. Действительно, если удастся выявить патогномоничные для развития АГ изменения эндотелиальной функции, — это позволит прояснить патогенетические основы заболевания и разработать адекватные медикаментозные схемы терапии. В обзоре рассмотрены накопленные на настоящее время данные по участию эндотелиальных клеток (ЭК) в развитии ГБ. Показан вклад изменений липидного обмена в физиологическое состояние эндотелиальной выстилки. Освещена роль нарушений эндотелиальной функции в увеличении продукции активных форм кислорода и дефектов метаболизма оксида азота. Продемонстрирована изученная авторскими коллективами активность следующих ферментных систем: НАДФН (никотинамидадениндинуклеотидфосфат)-оксидазы, циклооксигеназы, кcантиноксидоредуктазы и эндотелиальной NO-синтазы. Взаимодействие эндотелия и внеклеточного матрикса, а также эндотелия и гладкомышечных клеток также приведено согласно литературным данным. Освещена роль грелина, продуцируемого эндотелием в регуляции сосудистого тонуса. Показаны методические подходы к изучению ЭК in vitro в условиях гипоксии. Основным итогом проведенного анализа литературных данных является необходимость исследования функции эндотелия в условиях гипоксии in vitro, а также влияние тканевой и гемической гипоксии in vivo, что позволит установить вклад функциональных нарушений эндотелия в развитие ГБ.

Endothelium is a multilevel cellular structure that permeates all organs and systems of the body. A disorder of the regulation of the arterial tone underlies essential hypertension. However, its pathogenesis basis, despite intense efforts, remains unclear. The unfavorable role of emotional stress, hypodynamia, obesity and disorder of water-salt metabolism is obvious. However, the exact mechanisms and predictors of the development of arterial hypertension (HTN) are not currently defined. This opposes the prevention and detection of essential hypertension at an early stage. The investigation of endothelial function as a target and a predisposing factor for HTN development is promising and implies both scientific and applied clinical significance. Indeed, understanding of pathognomonic endothelial alterations for HTN development will clarify its pathogenesis and will help the development of the adequate treatment protocols. The paper reviews current data on the involvement of endothelial cells (EC) in the development of HTN. The role of lipid disorders in the physiological state of the endothelium is shown. The role of endothelial dysfunction in increasing production of active oxygen species and disorders in the nitric oxide metabolism is highlighted. The activity of the following enzyme is reviewed: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, cyclooxygenase, xantinoxydoreductase and endothelial NO synthase. The interaction of the endothelium and the extracellular matrix, as well as endothelium and smooth muscle cells, is also given according to the literature data. The role of ghrelin, produced by endothelium, in the regulation of vascular tone is highlighted. Methods of the EC assessment in vitro under hypoxia are presented. Based on the literature review, it is clear that the assessment of the endothelium under hypoxia is highly important, as well as the investigation of the influence of tissue and hemic hypoxia in vivo. These studies will help to establish the contribution of functional endothelial disturbances to the development of HTN.

артериальная гипертензиягипертоническая болезньэндотелийэндотелиальные клеткиarterial hypertensionessential hypertensionendotheliumendothelial cellsReferencesLubrano V, Balzan S. Roles of LOX-1 in microvascular dysfunction. Microvasc Res. 2016;105:132–40. doi:10.1016/j. mvr.2016.02.006Lubrano V, Balzan S. Roles of LOX-1 in microvascular dysfunction. Microvasc Res. 2016;105:132–40. doi:10.1016/j. mvr.2016.02.006Chen M, Masaki T, SawamuraT. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 2002;95(1):89–100.Chen M, Masaki T, SawamuraT. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 2002;95(1):89–100.Kenney WL, Cannon JG, Alexander LM. Cutaneous microvascular dysfunction correlates with serum LDL and sLOX-1 receptor concentrations. Microvasc Res. 2013;85:112–17. doi:10.1016/j.mvr.2012.10.010Kenney WL, Cannon JG, Alexander LM. Cutaneous microvascular dysfunction correlates with serum LDL and sLOX-1 receptor concentrations. Microvasc Res. 2013;85:112–17. doi:10.1016/j.mvr.2012.10.010Holowatz LA, Santhanam L, Webb A, Berkowitz DE, Kenney WL. Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans. J Physiol. 2011;589(Pt 8):2093–103. doi:10.1113/jphysiol.2010.203935Holowatz LA, Santhanam L, Webb A, Berkowitz DE, Kenney WL. Oral atorvastatin therapy restores cutaneous microvascular function by decreasing arginase activity in hypercholesterolaemic humans. J Physiol. 2011;589(Pt 8):2093–103. doi:10.1113/jphysiol.2010.203935García-Redondo AB, Aguado A, Briones AM, Salaices M. NADPH oxidases and vascular remodeling in cardiovascular diseases. Pharmacol Res. 2016;114:110–20. doi:10.1016/j. phrs.2016.10.015García-Redondo AB, Aguado A, Briones AM, Salaices M. NADPH oxidases and vascular remodeling in cardiovascular diseases. Pharmacol Res. 2016;114:110–20. doi:10.1016/j. phrs.2016.10.015Forte M, Nocella C, De Falco E, Palmerio S, Schirone L, Valenti V et al. The pathophysiological role of NOX2 in hypertension and organ damage. High Blood Press Cardiovasc Prev. 2016;23 (4):355–64. doi:10.1007/s40292–016–0175-yForte M, Nocella C, De Falco E, Palmerio S, Schirone L, Valenti V et al. The pathophysiological role of NOX2 in hypertension and organ damage. High Blood Press Cardiovasc Prev. 2016;23 (4):355–64. doi:10.1007/s40292–016–0175-ySahoo S, Meijles DN, Pagano PJ. NADPH oxidases: key modulators in aging and age-related cardiovascular diseases? Clin Sci (Lond). 2016;130(5):317–35. doi:10.1042/CS20150087Sahoo S, Meijles DN, Pagano PJ. NADPH oxidases: key modulators in aging and age-related cardiovascular diseases? Clin Sci (Lond). 2016;130(5):317–35. doi:10.1042/CS20150087Nurkiewicz TR, Wu G, Li P, Boegehold MA. Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt. Microcirculation. 2010;17(2):147–57. doi:10.1111/j.1549–8719.2009.00014.xNurkiewicz TR, Wu G, Li P, Boegehold MA. Decreased arteriolar tetrahydrobiopterin is linked to superoxide generation from nitric oxide synthase in mice fed high salt. Microcirculation. 2010;17(2):147–57. doi:10.1111/j.1549–8719.2009.00014.xChannon KM. Tetrahydrobiopterin: Regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med. 2004;14(8):323–27. doi:10.1016/j.tcm.2004.10.003Channon KM. Tetrahydrobiopterin: Regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med. 2004;14(8):323–27. doi:10.1016/j.tcm.2004.10.003Dinh QN, Drummond GR, Sobey CG, Chrissobolis S. Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. Biomed Res Int. 2014;2014:406960. doi:10.1155/ 2014/406960Dinh QN, Drummond GR, Sobey CG, Chrissobolis S. Roles of inflammation, oxidative stress, and vascular dysfunction in hypertension. Biomed Res Int. 2014;2014:406960. doi:10.1155/ 2014/406960Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004;56(3):387–437. doi:10.1124/pr.56.3.3Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004;56(3):387–437. doi:10.1124/pr.56.3.3Feletou M, Huang Y, Vanhoutte PM. Endotheliummediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol. 2011;164(3):894–912. doi:10.1111/j.1476–5381. 2011.01276.xFeletou M, Huang Y, Vanhoutte PM. Endotheliummediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol. 2011;164(3):894–912. doi:10.1111/j.1476–5381. 2011.01276.xVirdis A, Taddei S. Endothelial dysfunction in resistance arteries of hypertensive humans: old and new conspirators. J Cardiovasc Pharmacol. 2016;67(6):451–57. doi:10.1097/FJC. 0000000000000362Virdis A, Taddei S. Endothelial dysfunction in resistance arteries of hypertensive humans: old and new conspirators. J Cardiovasc Pharmacol. 2016;67(6):451–57. doi:10.1097/FJC. 0000000000000362Kelley EE. A new paradigm for XOR-catalyzed reactive species generation in the endothelium. Pharmacol Rep. 2015;67 (4):669–74. doi:10.1016/j.pharep.2015.05.004Kelley EE. A new paradigm for XOR-catalyzed reactive species generation in the endothelium. Pharmacol Rep. 2015;67 (4):669–74. doi:10.1016/j.pharep.2015.05.004Enroth C, Eger BT, Okamoto K, Nishino T, Nishino T, Pai EF. Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: Structure-based mechanism of conversion. Proc Natl Acad Sci USA. 2000;97(20):10723–8.Enroth C, Eger BT, Okamoto K, Nishino T, Nishino T, Pai EF. Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: Structure-based mechanism of conversion. Proc Natl Acad Sci USA. 2000;97(20):10723–8.Maia LB, Moura JJ. Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases. J Biol Inorg Chem. 2011;16(3):443–460. doi:10.1007/s00775–010–0741-zMaia LB, Moura JJ. Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases. J Biol Inorg Chem. 2011;16(3):443–460. doi:10.1007/s00775–010–0741-zKojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660. doi:10.1038/45230Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone releasing acylated peptide from stomach. Nature. 1999;402(6762):656–660. doi:10.1038/45230Kleinz MJ, Maguire JJ, Skepper JN, Davenport AP. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res. 2006;69(1):227–35. doi:10.1016/j. cardiores.2005.09.001Kleinz MJ, Maguire JJ, Skepper JN, Davenport AP. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res. 2006;69(1):227–35. doi:10.1016/j. cardiores.2005.09.001Iglesias MJ, Pineiro R, Blanco M, Gallego R, Diéguez C, Gualillo O et al. Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovasc Res. 2004;62(93):481–488. doi:10.1016/j.cardiores.2004.01.024Iglesias MJ, Pineiro R, Blanco M, Gallego R, Diéguez C, Gualillo O et al. Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovasc Res. 2004;62(93):481–488. doi:10.1016/j.cardiores.2004.01.024Tesauro M, Schinzari F, Iantorno M, Rizza S, Melina D, Lauro D et al. Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation. 2005;112(19):2986–92. doi:10.1161/circulationaha.105.553883Tesauro M, Schinzari F, Iantorno M, Rizza S, Melina D, Lauro D et al. Ghrelin improves endothelial function in patients with metabolic syndrome. Circulation. 2005;112(19):2986–92. doi:10.1161/circulationaha.105.553883Kawczynska-Drozdz A, Olszanecki R, Jawien J, Brzozowski T, Pawlik WW, Korbut R et al. Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats. Am J Hypertens. 2006;19(7):764–7. doi:10.1016/j.amjhyper.2006.01.022Kawczynska-Drozdz A, Olszanecki R, Jawien J, Brzozowski T, Pawlik WW, Korbut R et al. Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats. Am J Hypertens. 2006;19(7):764–7. doi:10.1016/j.amjhyper.2006.01.022Tesauro M, Schinzari F, Rovella V, Di Daniele N, Lauro D, Mores N et al. Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity-related metabolic syndrome. Hypertension. 2009;54(5):995–1000. doi:10.1161/HYPERTENSIONAHA. 109.137729Tesauro M, Schinzari F, Rovella V, Di Daniele N, Lauro D, Mores N et al. Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity-related metabolic syndrome. Hypertension. 2009;54(5):995–1000. doi:10.1161/HYPERTENSIONAHA. 109.137729de Wit C, Griffith TM. Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses. Pflugers Arch. 2010;459(6):897–914. doi:10.1007/s00424–010–0830–4de Wit C, Griffith TM. Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses. Pflugers Arch. 2010;459(6):897–914. doi:10.1007/s00424–010–0830–4Maguire JJ, Skepper JN, Skepper JN, Davenport AP. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res. 2006;69(1):227–235.Maguire JJ, Skepper JN, Skepper JN, Davenport AP. Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man. Cardiovasc Res. 2006;69(1):227–235.Félétou M, Vanhoutte PM. Endothelium-dependent hyperpolarizations: past beliefs and present facts. Ann Med. 2007;39 (7):495–516.Félétou M, Vanhoutte PM. Endothelium-dependent hyperpolarizations: past beliefs and present facts. Ann Med. 2007;39 (7):495–516.Chou TC, Yen MH, Li CY, Ding YA. Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension. 1998;31(2):643–8.Chou TC, Yen MH, Li CY, Ding YA. Alterations of nitric oxide synthase expression with aging and hypertension in rats. Hypertension. 1998;31(2):643–8.Kondrashov A, Vrankova S, Dovinová I, Sevčík R, Parohová J, Barta A et al. The effects of new Alibernet red wine extract on nitric oxide and reactive oxygen species production in spontaneously hypertensive rats. Oxid Med Cell Longev. 2012; 2012:806285. doi:10.1155/2012/806285Kondrashov A, Vrankova S, Dovinová I, Sevčík R, Parohová J, Barta A et al. The effects of new Alibernet red wine extract on nitric oxide and reactive oxygen species production in spontaneously hypertensive rats. Oxid Med Cell Longev. 2012; 2012:806285. doi:10.1155/2012/806285Nava E, Noll G, Luscher TF. Increased activity of constitutive nitric oxide synthase in cardiac endothelium in spontaneous hypertension. Circulation. 1995;91(9):2310–3.Nava E, Noll G, Luscher TF. Increased activity of constitutive nitric oxide synthase in cardiac endothelium in spontaneous hypertension. Circulation. 1995;91(9):2310–3.Al-Gburi S, Deussen A, Zatschler B, Weber S, Künzel S, El-Armouche A et al. Sex-difference in expression and function of beta-adrenoceptors in macrovessels: role of the endothelium. Basic Res Cardiol. 2017;112(3):29. doi:10.1007/s00395–017–0617–2Al-Gburi S, Deussen A, Zatschler B, Weber S, Künzel S, El-Armouche A et al. Sex-difference in expression and function of beta-adrenoceptors in macrovessels: role of the endothelium. Basic Res Cardiol. 2017;112(3):29. doi:10.1007/s00395–017–0617–2Caniffi C, Cerniello FM, Gobetto MN, Sueiro ML, Costa MA, Arranz C. Vascular tone regulation induced by C-type natriuretic peptide: differences in endothelium-dependent and independent mechanisms involved in normotensive and spontaneously hypertensive rats. PLoS One. 2016;11(12):e0167817. doi:10.1371/journal.pone.0167817Caniffi C, Cerniello FM, Gobetto MN, Sueiro ML, Costa MA, Arranz C. Vascular tone regulation induced by C-type natriuretic peptide: differences in endothelium-dependent and independent mechanisms involved in normotensive and spontaneously hypertensive rats. PLoS One. 2016;11(12):e0167817. doi:10.1371/journal.pone.0167817Nakao K, Kuwahara K, Nishikimi T, Nakagawa Y, Kinoshita H, Minami T et al. Endothelium-derived C-type natriuretic peptide contributes to blood pressure regulation by maintaining endothelial integrity. Hypertension. 2017;69(2):286– 296. doi:10.1161/HYPERTENSIONAHA.116.08219Nakao K, Kuwahara K, Nishikimi T, Nakagawa Y, Kinoshita H, Minami T et al. Endothelium-derived C-type natriuretic peptide contributes to blood pressure regulation by maintaining endothelial integrity. Hypertension. 2017;69(2):286– 296. doi:10.1161/HYPERTENSIONAHA.116.08219Harvey A, Montezano AC, Lopes RA, Rios F, Touyz RM. Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications Can J Cardiol. 2016;32(5):659–68. doi:10. 1016/j.cjca.2016.02.070Harvey A, Montezano AC, Lopes RA, Rios F, Touyz RM. Vascular fibrosis in aging and hypertension: molecular mechanisms and clinical implications Can J Cardiol. 2016;32(5):659–68. doi:10. 1016/j.cjca.2016.02.070Gutterman DD, Chabowski DS, Kadlec AO, Durand MJ, Freed JK, Ait-Aissa K et al. The human microcirculation. Regulation of flow and beyond. Circ Res. 2016;118(1):157–72. doi:10.1161/CIRCRESAHA.115.305364Gutterman DD, Chabowski DS, Kadlec AO, Durand MJ, Freed JK, Ait-Aissa K et al. The human microcirculation. Regulation of flow and beyond. Circ Res. 2016;118(1):157–72. doi:10.1161/CIRCRESAHA.115.305364Fruchart JC. Peroxisome proliferatoractivated receptoralpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis. 2009;205(1):1–8. doi:10.1016/j.atherosclerosis.2009.03.008Fruchart JC. Peroxisome proliferatoractivated receptoralpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis. 2009;205(1):1–8. doi:10.1016/j.atherosclerosis.2009.03.008Glineur C, Gross B, Neve B, Rommens C, Chew GT, Martin-Nizard F et al. Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33(3):621–8. doi:10.1161/ ATVBAHA.112.300665Glineur C, Gross B, Neve B, Rommens C, Chew GT, Martin-Nizard F et al. Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33(3):621–8. doi:10.1161/ ATVBAHA.112.300665Jíchová Š, Doleželová Š, Kopkan L, KompanowskaJezierska E, Sadowski J, Červenka L. Fenofibrate attenuates malignant hypertension by suppression of the renin-angiotensin system: a study in Cyp1a1-Ren-2 transgenic rats. Am J Med Sci. 2016;352(6):618–630. doi:10.1016/j.amjms.2016.09.008Jíchová Š, Doleželová Š, Kopkan L, KompanowskaJezierska E, Sadowski J, Červenka L. Fenofibrate attenuates malignant hypertension by suppression of the renin-angiotensin system: a study in Cyp1a1-Ren-2 transgenic rats. Am J Med Sci. 2016;352(6):618–630. doi:10.1016/j.amjms.2016.09.008Kvandová M, Majzúnová M, Dovinová I. The role of PPARgamma in cardiovascular diseases. Physiol Res. 2016;65 (S3): S343-S363.Kvandová M, Majzúnová M, Dovinová I. The role of PPARgamma in cardiovascular diseases. Physiol Res. 2016;65 (S3): S343-S363.Nauta TD, van den Broek M, Gibbs S, van der Pouw-Kraan TC, Oudejans CB, van Hinsbergh VW et al. Identification of HIF-2αregulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis. 2017;20 (1):39–54. doi:10.1007/s10456–016–9527–4Nauta TD, van den Broek M, Gibbs S, van der Pouw-Kraan TC, Oudejans CB, van Hinsbergh VW et al. Identification of HIF-2αregulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis. 2017;20 (1):39–54. doi:10.1007/s10456–016–9527–4Befani C, Liakos P. Hypoxia upregulates integrin gene expression in microvascular endothelial cells and promotes their migration and capillary-like tube formation. Cell Biol Int. 2017;41 (7):769–778.Befani C, Liakos P. Hypoxia upregulates integrin gene expression in microvascular endothelial cells and promotes their migration and capillary-like tube formation. Cell Biol Int. 2017;41 (7):769–778.Daiber A, Di Lisa F, Oelze M, Kröller-Schön S, Steven S, Schulz E et al. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. Br J Pharmacol. 2017;174(12):1670–1689. doi:10.1111/bph.13403Daiber A, Di Lisa F, Oelze M, Kröller-Schön S, Steven S, Schulz E et al. Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function. Br J Pharmacol. 2017;174(12):1670–1689. doi:10.1111/bph.13403Koziel A, Jarmuszkiewicz W. Hypoxia and aerobic metabolism adaptations of human endothelial cells. Pflugers Arch. 2017;469(5–6):815–27. doi:10.1007/s00424–017–1935–9Koziel A, Jarmuszkiewicz W. Hypoxia and aerobic metabolism adaptations of human endothelial cells. Pflugers Arch. 2017;469(5–6):815–27. doi:10.1007/s00424–017–1935–9Hernansanz-Agustín P, Ramos E, Navarro E, Parada E, Sánchez-López N, Peláez-Aguado L et al. Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia. Redox Biol. 2017;12:1040–1051. doi:10.1016/j. redox.2017.04.025Hernansanz-Agustín P, Ramos E, Navarro E, Parada E, Sánchez-López N, Peláez-Aguado L et al. Mitochondrial complex I deactivation is related to superoxide production in acute hypoxia. Redox Biol. 2017;12:1040–1051. doi:10.1016/j. redox.2017.04.025Biancardi VC, Bomfim GF, Reis WL, Al-Gassimi S, Nunes KP. The interplay between Angiotensin II, TLR4 and hypertension. Pharmacol Res. 2017;120:88–96. doi:10.1016/j.phrs.2017.03.017Biancardi VC, Bomfim GF, Reis WL, Al-Gassimi S, Nunes KP. The interplay between Angiotensin II, TLR4 and hypertension. Pharmacol Res. 2017;120:88–96. doi:10.1016/j.phrs.2017.03.017De Batista PR, Palacios R, Martín A, Hernanz R, Médici CT, Silva MA et al. Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production. PloS One. 2014;9(8): e104020. doi:10.1371/journal.pone.0104020De Batista PR, Palacios R, Martín A, Hernanz R, Médici CT, Silva MA et al. Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production. PloS One. 2014;9(8): e104020. doi:10.1371/journal.pone.0104020Bomfim GF, Dos Santos RA, Oliveira MA, Giachini FR, Akamine EH, Tostes RC et al. Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin Sci (Lond). 2012;122(12):535–543. doi:10.1111/bph.13117Bomfim GF, Dos Santos RA, Oliveira MA, Giachini FR, Akamine EH, Tostes RC et al. Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin Sci (Lond). 2012;122(12):535–543. doi:10.1111/bph.13117Hernanz R, Martinez-Revelles S, Palacios R, Martin A, Cachofeiro V, Aguado A et al. Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin IIinduced hypertension. Br J Pharmacol. 2015;172(12):3159–3176. doi:10.1111/bph.13117Hernanz R, Martinez-Revelles S, Palacios R, Martin A, Cachofeiro V, Aguado A et al. Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin IIinduced hypertension. Br J Pharmacol. 2015;172(12):3159–3176. doi:10.1111/bph.13117Bomfim GF, Echem C, Martins CB, Costa TJ, Sartoretto SM, Dos Santos RA et al. Toll-like receptor 4 inhibition reduces vas cular inflammation in spontaneously hypertensive rats. Life Sci. 2015;122:1–7. doi:10.1016/j.lfs.2014.12.001Bomfim GF, Echem C, Martins CB, Costa TJ, Sartoretto SM, Dos Santos RA et al. Toll-like receptor 4 inhibition reduces vas cular inflammation in spontaneously hypertensive rats. Life Sci. 2015;122:1–7. doi:10.1016/j.lfs.2014.12.001McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC et al. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res. 2015;107(1):119– 130. doi:10.1093/cvr/cvv137McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC et al. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res. 2015;107(1):119– 130. doi:10.1093/cvr/cvv137Mian MO, Barhoumi T, Briet M, Paradis P, Schiffrin EL. Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses. J Hypertens. 2016;34(1):97–108. doi:10.1097/HJH.0000000000000761Mian MO, Barhoumi T, Briet M, Paradis P, Schiffrin EL. Deficiency of T-regulatory cells exaggerates angiotensin II-induced microvascular injury by enhancing immune responses. J Hypertens. 2016;34(1):97–108. doi:10.1097/HJH.0000000000000761

The authors declare that there are no conflicts of interest present.