4703
J Physiol 594.17 (2016) pp 4703–4704
PERSPECTIVES
Now you see it, now you don’t: the changing face of endothelin-1 signalling during vascular ontogenesis Simon Bulley and Jonathan H. Jaggar Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Suite 426, Memphis, TN 38163, USA
The Journal of Physiology
Email: [email protected]
Multiple cell types, including those located in the cardiovascular system, can undergo functional development in the early postnatal period. For example, acetylcholine, a recognized endothelium-dependent vasodilator in adult arteries, is ineffective in newborn (P1) arteries (Flavahan et al. 2013). By postnatal day 7 (P7), NO-mediated dilatation to acetylcholine is present due to upregulated signalling to endothelial NO synthase (eNOS) (Flavahan et al. 2013). Endothelin-1 (ET-1), a potent vasoconstrictor generated from its precursor Big ET-1, is the most predominant of the three members of the endothelin family produced by endothelial cells. It binds to endothelin receptors located on both endothelial cells and other nearby cell types and acts in an autocrine and paracrine manner. ET-1 binding to endothelin-A (ETA ) and endothelin-B (ETB ) receptors on vascular smooth muscle cells stimulates vasoconstriction (Marasciulo et al. 2006). In contrast, ETB receptor activation on endothelial cells leads to NO generation, which causes vasodilatation. ET-1 causes transient vasodilatation followed by prolonged vasoconstriction and stimulates both endothelial and smooth muscle cell proliferation. Altered ET-1 signalling and expression is associated with numerous cardiovascular diseases, including hypertension, atherosclerosis and heart failure (Marasciulo et al. 2006). Plasma ET-1 levels are elevated during embryonic and fetal development. However, whether endothelial cells of newborn arteries express and release ET-1 to stimulate constriction was unclear. In this issue of The Journal of Physiology, Chang et al. (2016) demonstrate
that newborn (P1) endothelial cells release ET-1 in response to stimulation by A23187, a Ca2+ ionophore, or thrombin, which binds to protease-activated receptors (PARs), resulting in mouse carotid artery constriction. By P7, ET-1-induced vasoconstriction is lost and by P21, endothelial stimulation by A23187 and thrombin results in vasodilatation, a shift that continues into adulthood. In contrast, exogenous ET-1 constricted carotid arteries from P1, P7 and P21 mice. Consistent with these results, thrombin released ET-1 from P1 arteries, but not from P21 arteries. The authors conclude from these results that these differing responses are due to a shift in endothelium-derived ET-1 generation during development. Chang et al. propose that increasing levels of endogenous NO during development may antagonize ET-1-mediated constriction through multiple mechanisms, including suppression of ET-1 exocytosis and expression. The robust stimulation of ET-1 release from newborn endothelial cells and associated vasoconstriction may not only be essential for physiological regulation of arterial contractility, but may also be associated with pathological responses. The article by Chang et al. is a carefully performed, informative study that not only derives new information, but opens up many new questions. Carotid arteries studied here are conduit vessels that stabilize pulsatile blood pressure during the cardiac cycle, but their contribution to blood pressure and regulation of brain blood flow are minimal. It would be interesting to determine whether neonatal endothelial cells lining resistance-size arteries that control systemic blood pressure and regional brain blood flow also express higher levels of ET-1 than those from mature arteries. A steady increase in systemic blood pressure occurs during fetal development and it is possible and worth studying whether resistance arteries undergo similar changes in endogenous ET-1 production and signalling that contribute during this developmental period. Arteries from specific anatomical locations, including the cerebral, pulmonary, coronary and mesenteric circulations, can respond differently to the same stimulus. During
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
development, the contribution of NO to endothelium-dependent dilatation also varies depending on the vascular bed involved. It would be fascinating to determine whether the results reported here translate to arteries in different anatomical locations. ET-1 release is regulated by several stimuli, including sheer stress, adrenaline (epinephrine), angiotensin II, growth factors, cytokines and free radicals (Marasciulo et al. 2006). Future studies are warranted to determine whether the stimulation of ET-1 release is thrombin-specific in newborn arteries. Thrombin stimulates Rho/ROCK and ET-1 synthesis. Flavahan & Flavahan (2014) have previously demonstrated that Rho/ROCK signalling is higher in newborn arteries than at P7, mirroring the loss of endothelial ET-1 expression. Conceivably, PAR expression and function may shift during the postnatal period, similar to changes in Rho/ROCK signalling and ET-1-induced constriction. It is plausible that endogenous ET-1 release controls the expression of endothelin ETA and ETB receptors during development, another possibility that should be studied. The present study focused on changes in ET-1 signalling during early development, but a shift during ageing also occurs. For example, ET-1 release is higher in arteries of aged (20 months) rats than younger (3–4 months) individuals, but the mechanisms involved and pathological relevance require further study (Goel et al. 2010). Answering questions such as these will further expand knowledge of the changing face of ET-1 signalling during vascular ontogenesis. References Chang F, Flavahan S & Flavahan NA (2016). Immature endothelial cells initiate endothelin-mediated constriction of newborn arteries. J Physiol 594, 4933–4944. Flavahan S & Flavahan NA (2014). The atypical structure and function of newborn arterial endothelium is mediated by Rho/Rho kinase signaling. Am J Physiol Heart Circ Physiol 307, H628–H632. Flavahan S, Mozayan MM, Lindgren I & Flavahan NA (2013). Pressure-induced maturation of endothelial cells on newborn mouse carotid arteries. Am J Physiol Heart Circ Physiol 305, H321–H329.
DOI: 10.1113/JP272564
4704 Goel A, Su B, Flavahan S, Lowenstein CJ, Berkowitz DE & Flavahan NA (2010). Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries.Circ Res 107, 242–251.
Perspectives Marasciulo F, Montagnani M & Potenza MA (2006). Endothelin-1: the yin and yang on vascular function. Curr Med Chem 13, 1655–1665.
J Physiol 594.17
Additional information Competing interests
None declared.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
J Physiol 594.17 (2016) pp 4703–4704
PERSPECTIVES
Now you see it, now you don’t: the changing face of endothelin-1 signalling during vascular ontogenesis Simon Bulley and Jonathan H. Jaggar Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Suite 426, Memphis, TN 38163, USA
The Journal of Physiology
Email: [email protected]
Multiple cell types, including those located in the cardiovascular system, can undergo functional development in the early postnatal period. For example, acetylcholine, a recognized endothelium-dependent vasodilator in adult arteries, is ineffective in newborn (P1) arteries (Flavahan et al. 2013). By postnatal day 7 (P7), NO-mediated dilatation to acetylcholine is present due to upregulated signalling to endothelial NO synthase (eNOS) (Flavahan et al. 2013). Endothelin-1 (ET-1), a potent vasoconstrictor generated from its precursor Big ET-1, is the most predominant of the three members of the endothelin family produced by endothelial cells. It binds to endothelin receptors located on both endothelial cells and other nearby cell types and acts in an autocrine and paracrine manner. ET-1 binding to endothelin-A (ETA ) and endothelin-B (ETB ) receptors on vascular smooth muscle cells stimulates vasoconstriction (Marasciulo et al. 2006). In contrast, ETB receptor activation on endothelial cells leads to NO generation, which causes vasodilatation. ET-1 causes transient vasodilatation followed by prolonged vasoconstriction and stimulates both endothelial and smooth muscle cell proliferation. Altered ET-1 signalling and expression is associated with numerous cardiovascular diseases, including hypertension, atherosclerosis and heart failure (Marasciulo et al. 2006). Plasma ET-1 levels are elevated during embryonic and fetal development. However, whether endothelial cells of newborn arteries express and release ET-1 to stimulate constriction was unclear. In this issue of The Journal of Physiology, Chang et al. (2016) demonstrate
that newborn (P1) endothelial cells release ET-1 in response to stimulation by A23187, a Ca2+ ionophore, or thrombin, which binds to protease-activated receptors (PARs), resulting in mouse carotid artery constriction. By P7, ET-1-induced vasoconstriction is lost and by P21, endothelial stimulation by A23187 and thrombin results in vasodilatation, a shift that continues into adulthood. In contrast, exogenous ET-1 constricted carotid arteries from P1, P7 and P21 mice. Consistent with these results, thrombin released ET-1 from P1 arteries, but not from P21 arteries. The authors conclude from these results that these differing responses are due to a shift in endothelium-derived ET-1 generation during development. Chang et al. propose that increasing levels of endogenous NO during development may antagonize ET-1-mediated constriction through multiple mechanisms, including suppression of ET-1 exocytosis and expression. The robust stimulation of ET-1 release from newborn endothelial cells and associated vasoconstriction may not only be essential for physiological regulation of arterial contractility, but may also be associated with pathological responses. The article by Chang et al. is a carefully performed, informative study that not only derives new information, but opens up many new questions. Carotid arteries studied here are conduit vessels that stabilize pulsatile blood pressure during the cardiac cycle, but their contribution to blood pressure and regulation of brain blood flow are minimal. It would be interesting to determine whether neonatal endothelial cells lining resistance-size arteries that control systemic blood pressure and regional brain blood flow also express higher levels of ET-1 than those from mature arteries. A steady increase in systemic blood pressure occurs during fetal development and it is possible and worth studying whether resistance arteries undergo similar changes in endogenous ET-1 production and signalling that contribute during this developmental period. Arteries from specific anatomical locations, including the cerebral, pulmonary, coronary and mesenteric circulations, can respond differently to the same stimulus. During
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
development, the contribution of NO to endothelium-dependent dilatation also varies depending on the vascular bed involved. It would be fascinating to determine whether the results reported here translate to arteries in different anatomical locations. ET-1 release is regulated by several stimuli, including sheer stress, adrenaline (epinephrine), angiotensin II, growth factors, cytokines and free radicals (Marasciulo et al. 2006). Future studies are warranted to determine whether the stimulation of ET-1 release is thrombin-specific in newborn arteries. Thrombin stimulates Rho/ROCK and ET-1 synthesis. Flavahan & Flavahan (2014) have previously demonstrated that Rho/ROCK signalling is higher in newborn arteries than at P7, mirroring the loss of endothelial ET-1 expression. Conceivably, PAR expression and function may shift during the postnatal period, similar to changes in Rho/ROCK signalling and ET-1-induced constriction. It is plausible that endogenous ET-1 release controls the expression of endothelin ETA and ETB receptors during development, another possibility that should be studied. The present study focused on changes in ET-1 signalling during early development, but a shift during ageing also occurs. For example, ET-1 release is higher in arteries of aged (20 months) rats than younger (3–4 months) individuals, but the mechanisms involved and pathological relevance require further study (Goel et al. 2010). Answering questions such as these will further expand knowledge of the changing face of ET-1 signalling during vascular ontogenesis. References Chang F, Flavahan S & Flavahan NA (2016). Immature endothelial cells initiate endothelin-mediated constriction of newborn arteries. J Physiol 594, 4933–4944. Flavahan S & Flavahan NA (2014). The atypical structure and function of newborn arterial endothelium is mediated by Rho/Rho kinase signaling. Am J Physiol Heart Circ Physiol 307, H628–H632. Flavahan S, Mozayan MM, Lindgren I & Flavahan NA (2013). Pressure-induced maturation of endothelial cells on newborn mouse carotid arteries. Am J Physiol Heart Circ Physiol 305, H321–H329.
DOI: 10.1113/JP272564
4704 Goel A, Su B, Flavahan S, Lowenstein CJ, Berkowitz DE & Flavahan NA (2010). Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries.Circ Res 107, 242–251.
Perspectives Marasciulo F, Montagnani M & Potenza MA (2006). Endothelin-1: the yin and yang on vascular function. Curr Med Chem 13, 1655–1665.
J Physiol 594.17
Additional information Competing interests
None declared.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
