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Neuropeptide Y: An Adrenergic Cotransmitter, Vasoconstrictor, and a Nerve-Derived Vascular Growth Factor
NPY: Adrenergic. Cotransmiaer, Vasoconstrictor, Nerve-Derived Vascular Growth
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19. von Kugelgen, I., Kurz, K., and Starke, K. (1993). Axon terminal P,-purinoceptors in feedback control of sympathetic transmitter release. Neuroscience 56, 263-267. 20. Fujioka, M., Cheung, D. W. (1987). Autoregulation of neuromuscular transmission in the guinea-pig saphenous artery. Eur. J . Pharmacol. 139, 147-153. 21. Todorov, L., Bjur, R., and Westfall, D. P. (1995). Modulation of sympathetic cotransmission by endogenous ATP and NE. FASEB 1. 9, A371. 22. Driessen, B., Bultmann, R., Gongalves, J., and Starke, K. (1996). Opposite modulation of noradrenaline and ATP release in guinea-pig vas deferens through prejunctional Padrenoceptors: Evidence for the /'3> subtype. N a m y n Schmiedebergs Arch. Pharmacol. 353, 564-571. 23. Gonsalves, J., Bultmann, R., and Driessen, B. (1996). Opposite modulation of cotransmitter
release in guinea-pig vas deferens: Increase of noradrenaline and decrease of ATP release by activation of prej unctional P-adrenoceptors. Naunyn Schmiedebergs Arch. Pharmacol. 353,184-192. 24. Driessen, B., von Kugelgen, I., and Starke, K. (1994). PI-Purinoceptor-mediated modulation
of neural noradrenaline and ATP release in guinea-pig vas deferens. Naunyn Schmiedebergs Arch. Pharmacol. 350, 42-48. 25. Kirkpatrick, K., and Burnstock, G. (1987).sympathetic nerve-mediated release of ATP from the guinea-pig vas deferens is unaffected by reserpine. Eur. /. Pharmacol. 138, 207-214.
Zofia Zukowska-Grojec Department of Physiology and Biophysics Georgetown University Medical Center Washington, D.C.20007
Neuropeptide Y: An Adrenergic Cotransmitter, Vasoconstrictor, and a Nerve-Derived Vascular Growth Factor The sympathetic nerves possess, in addition to norepinephrine (NE),several nonadrenergic cotransmitters, the major ones being purines and neuropeptide Y (NPY). NPY is, in fact, the most abundant peptide in the central and the sympathoadrenomedullary nervous systems, and its presence and structure are highly conserved throughout the evolution; for example, human and shark NPY differ only by three amino acids (1).Together with peptide YY and pancreatic polypeptide, they form a family of peptides that subserve pleiotropic functions of neurotransmitters, neuromodulators, hormones, and paracrine regulators. In addition to neuronal sources, NPY is present extraneuronally in AduanGes in Pharmacology, V o b m e 42 Copyright D 1998 by Academic Press. All right? of reproduction in any form reserved. 1054-3589198 $25.00
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Zofia Zukowska-Grojec
platelets, lymphocytes, and endothelial cells. Elevated levels of immunoreactive NPY are found during conditions of intense and prolonged sympathetic nerve activation, such as stress, exhaustive exercise, hypertension, and myocardial infarction (1).The functions of NPY as a sympathetic cotransmitter and a neuromodulator in the cardiovascular system have been extensively studied (1) and reviewed elsewhere in the book. This review briefly summarizes our studies of vascular actions of NPY (Fig. 1). NPY exerts multiple actions in blood vessels. Acutely, it causes vasoconstriction by activation of its specific Y1 receptors and potentiates the actions of other sympathetic and nonsympathetic vasoconstrictors (1).However, not all blood vessels are sensitive to NPY. While small resistance vessels in some vascular beds, such as cerebral, coronary, and splanchnic, are extremely sensitive to NPY, larger vessels, such as the aorta or the pulmonary arteries, are resistant to NPY-induced vasoconstriction (1).Recent discoveries of specific and Y1-selective receptor antagonists (2)corroborate these findings and indicate that endogenously released NPY does not contribute to resting vascular tone. Thus, in basal conditions, catecholamines appear to provide the primary neurogenic influence on blood vessels.
FIGURE I Vascular neural and paracrine NPY system. NPY is released from the sympathetic nerves, endothelium, and platelets and acts on Y 1 receptors to cause vasoconstriction and on Y1 and Y2 receptors to stimulate VSMC proliferation and endothelial angiogenesis. DPPIV and APP inactivate NPY as a Y1 agonist and convert it into a Y2 agonist. Additionally, circulating PYY mimics the NPY-Yl and -Y2 activities.
NPY: Adrenergic, Cotransmiaer. Vasoconstrictor, Nerve-Derived Vascular Growth
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However, the situation changes during stress and in other states where the sympathetic nerve activity becomes highly activated. In rats subjected to immobilization stress, which markedly elevates plasma catecholamine levels, pressor responses are blocked by combined a- and P-adrenergic blockade, but increases in vascular resistance in the superior mesenteric bed are not (2). Fifty percent of the mesenteric vasoconstriction is resistant to total adrenergic blockade (with prazosin, yohinibine, and propranolol) and also remains unchanged by blockade of vasopressin and angiotensin I1 receptors (2).Recently, we have confirmed that the nonadrenergic (cold) stress-mediated component of the mesenteric vasoconstriction is NPY-dependent and mediated by NPYY1 receptors (2). What determines increased vascular responsiveness to NPY during stress is not yet clear. It may simply be the result of greater NPY release and/or decreased peptide inactivation. While the former is true for many stress conditions, particularly when prolonged and exhaustive, the latter is not. In rats stressed by immobilization, NPY clearance appears to be increased in parallel to the increased release (1).Two ectopeptidases have been implicated in the process of NPY degradation ( 3 ) .Dipeptidyl peptidase IV (DPPIV) ( 3 ) ,a serine protease present on endothelial cells and activated lymphocytes (where it is known as cd26), cleaves Tyr-Pro ( 3 , 4) off of the NPY’s N-terminus, and aminopeptidase P (APP)( 3 ) ,present on vascular smooth-muscle cells (VSMCs), eliminates Tyr (4). The products of these enzyme reactions, C-terminal fragments of NPY devoid of Tyr (4),are no longer able to stimulate vasoconstrictive Y1 receptors but remain active at the Y2 receptors, which are believed to be nonvasoconstrictive. Thus, increased NPY degradation would presumably eliminate the vasoconstrictive activity of the peptide. Vascular responsiveness to NPY is increased not only in stress, but also in other states with elevated plasma catecholamine levels (e.g., in SHR). In endotoxemia, the NPY-mediated responsiveness is not augmented, yet NPY is the only agonist to which vessels do not develop desensitization (1).We hypothesized that high circulating catecholamine levels sensitize blood vessel to NPY. In support of this notion, we have previously found that prolonged exposure of blood vessels to NE markedly upregulates vasopressor responses in vivo and in uitro and augments calcium-stimulatory (CaZ+uptake into cultured VSMC) responses to NPY (1).This effect is long-lasting, resistant to adrenergic and calcium-channel blockers, and dependent on thapsigargin-sensitive intracellular calcium stores, indicating activation by NPY of a unique signaling pathway, distinct from that used by adrenergic agonists (1).The NE-induced sensitization to NPY is mediated by P2-adrenergic (mimicked by isoproterenol) and not al-adrenergic receptors and, in part, is due to stimulation of cyclic adenosine monophosphate. It appears, therefore, that vasoconstrictor hyperresponsiveness to NPY in hyperadrenergic states is due to P-adrenergic “priming” of VSMCs; the exact nature of this cross-talk remains to be established. The efficacy of NPY as a vasoconstrictor would then depend on several factors: the adrenergic status, the activity of NPY degrading enzymes, and the density the Y 1 receptors. Although low adrenergic activity, activation of peptidases, and low Y1 receptor density may eliminate NPY’s vasoconstrictor action, they do not abolish other vasoactive properties of the peptide. We
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Zofia Zukowska-Grojec
(1) have found, and others (4) have confirmed, that NPY stimulates VSMC proliferation independently of serum factors and with an efficacy similar to that of platelet-derived growth factor. The mitogenic effect of NPY is, in part, mimicked by the Y1- and, even more so, the Y2-receptor agonists, products of DPPIV and APP cleavage. Thus, these peptidases do not actually inactivate NPY but convert it to other biologically active forms. Finally, we have found that NPY exerts similar growth-promoting activity on endothelial cells and in vivo stimulates angiogenesis (5). As with the mitogenic effect in VSMCs, the angiogenic action of NPY is, in part, mimicked by Y1 and Y2 agonists (5). Whether this indicates that the growth promoting effects of NPY require cooperation of both receptors or that they are mediated by a novel receptor that recognizes both types of agonists, remains to be determined. Interestingly, the growth-promoting activities of NPY occur at concentrations much lower (< nm) that those required for vasoconstriction (>nM), suggesting that NPY may be foremost the nerve-derived trophic factor, and only at high levels of sympathetic nerve activity is released in large enough quantities to be vasoconstrictive. Thus, physiologically, NPY may be the mediator that regulates blood vessel growth and remodeling during development, the long-suspected sympathetic trophic factor. References 1. Zukowska-Grojec, Z., and Wahlestedt, C. (1993). Origin and actions of neuropeptide Y in the cardiovascular system. In The Biology of Neuropeptide Y and Related Peptides. (W. F. Colmers and C. Wahlestedt, eds.), pp. 315-338. Humana Press, Totowa, New Jersey. 2. Zukowska-Grojec, Z., Dayao, E. K., Karwatowska-Prokopczuk, E., Hauser, G. J., and Doods, H. N. (1996). Stress-induced mesenteric vasoconstriction in rats is mediated by neuropeptide Y Y1 receptors. Am. J. Physiol. , H796-H800. 3. Mentlein, R., Dahms, P., Grandt, D., and Kruger, R. (1993). Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul. Peptides 49, 133-144. 4. Erlinge, D., Brunkwall, J., and Edvinsson, L. (1994).Neuropeptide Y stimulates proliferation of human vascular smooth muscle cells: Cooperation with noradrenaline and ATP. Regul. Peptides 50, 259-265. 5 . Zukowska-Grojec, Z., Karwatowska-Prokopczuk, E., Yeh, Y-Y., Chen, W-T., Rose, W., and Grant, D. (1995).Endothelial neuropeptide Y (NPY) system and angiogenesis. Circulution 192, 3430.
I25
19. von Kugelgen, I., Kurz, K., and Starke, K. (1993). Axon terminal P,-purinoceptors in feedback control of sympathetic transmitter release. Neuroscience 56, 263-267. 20. Fujioka, M., Cheung, D. W. (1987). Autoregulation of neuromuscular transmission in the guinea-pig saphenous artery. Eur. J . Pharmacol. 139, 147-153. 21. Todorov, L., Bjur, R., and Westfall, D. P. (1995). Modulation of sympathetic cotransmission by endogenous ATP and NE. FASEB 1. 9, A371. 22. Driessen, B., Bultmann, R., Gongalves, J., and Starke, K. (1996). Opposite modulation of noradrenaline and ATP release in guinea-pig vas deferens through prejunctional Padrenoceptors: Evidence for the /'3> subtype. N a m y n Schmiedebergs Arch. Pharmacol. 353, 564-571. 23. Gonsalves, J., Bultmann, R., and Driessen, B. (1996). Opposite modulation of cotransmitter
release in guinea-pig vas deferens: Increase of noradrenaline and decrease of ATP release by activation of prej unctional P-adrenoceptors. Naunyn Schmiedebergs Arch. Pharmacol. 353,184-192. 24. Driessen, B., von Kugelgen, I., and Starke, K. (1994). PI-Purinoceptor-mediated modulation
of neural noradrenaline and ATP release in guinea-pig vas deferens. Naunyn Schmiedebergs Arch. Pharmacol. 350, 42-48. 25. Kirkpatrick, K., and Burnstock, G. (1987).sympathetic nerve-mediated release of ATP from the guinea-pig vas deferens is unaffected by reserpine. Eur. /. Pharmacol. 138, 207-214.
Zofia Zukowska-Grojec Department of Physiology and Biophysics Georgetown University Medical Center Washington, D.C.20007
Neuropeptide Y: An Adrenergic Cotransmitter, Vasoconstrictor, and a Nerve-Derived Vascular Growth Factor The sympathetic nerves possess, in addition to norepinephrine (NE),several nonadrenergic cotransmitters, the major ones being purines and neuropeptide Y (NPY). NPY is, in fact, the most abundant peptide in the central and the sympathoadrenomedullary nervous systems, and its presence and structure are highly conserved throughout the evolution; for example, human and shark NPY differ only by three amino acids (1).Together with peptide YY and pancreatic polypeptide, they form a family of peptides that subserve pleiotropic functions of neurotransmitters, neuromodulators, hormones, and paracrine regulators. In addition to neuronal sources, NPY is present extraneuronally in AduanGes in Pharmacology, V o b m e 42 Copyright D 1998 by Academic Press. All right? of reproduction in any form reserved. 1054-3589198 $25.00
I26
Zofia Zukowska-Grojec
platelets, lymphocytes, and endothelial cells. Elevated levels of immunoreactive NPY are found during conditions of intense and prolonged sympathetic nerve activation, such as stress, exhaustive exercise, hypertension, and myocardial infarction (1).The functions of NPY as a sympathetic cotransmitter and a neuromodulator in the cardiovascular system have been extensively studied (1) and reviewed elsewhere in the book. This review briefly summarizes our studies of vascular actions of NPY (Fig. 1). NPY exerts multiple actions in blood vessels. Acutely, it causes vasoconstriction by activation of its specific Y1 receptors and potentiates the actions of other sympathetic and nonsympathetic vasoconstrictors (1).However, not all blood vessels are sensitive to NPY. While small resistance vessels in some vascular beds, such as cerebral, coronary, and splanchnic, are extremely sensitive to NPY, larger vessels, such as the aorta or the pulmonary arteries, are resistant to NPY-induced vasoconstriction (1).Recent discoveries of specific and Y1-selective receptor antagonists (2)corroborate these findings and indicate that endogenously released NPY does not contribute to resting vascular tone. Thus, in basal conditions, catecholamines appear to provide the primary neurogenic influence on blood vessels.
FIGURE I Vascular neural and paracrine NPY system. NPY is released from the sympathetic nerves, endothelium, and platelets and acts on Y 1 receptors to cause vasoconstriction and on Y1 and Y2 receptors to stimulate VSMC proliferation and endothelial angiogenesis. DPPIV and APP inactivate NPY as a Y1 agonist and convert it into a Y2 agonist. Additionally, circulating PYY mimics the NPY-Yl and -Y2 activities.
NPY: Adrenergic, Cotransmiaer. Vasoconstrictor, Nerve-Derived Vascular Growth
I27
However, the situation changes during stress and in other states where the sympathetic nerve activity becomes highly activated. In rats subjected to immobilization stress, which markedly elevates plasma catecholamine levels, pressor responses are blocked by combined a- and P-adrenergic blockade, but increases in vascular resistance in the superior mesenteric bed are not (2). Fifty percent of the mesenteric vasoconstriction is resistant to total adrenergic blockade (with prazosin, yohinibine, and propranolol) and also remains unchanged by blockade of vasopressin and angiotensin I1 receptors (2).Recently, we have confirmed that the nonadrenergic (cold) stress-mediated component of the mesenteric vasoconstriction is NPY-dependent and mediated by NPYY1 receptors (2). What determines increased vascular responsiveness to NPY during stress is not yet clear. It may simply be the result of greater NPY release and/or decreased peptide inactivation. While the former is true for many stress conditions, particularly when prolonged and exhaustive, the latter is not. In rats stressed by immobilization, NPY clearance appears to be increased in parallel to the increased release (1).Two ectopeptidases have been implicated in the process of NPY degradation ( 3 ) .Dipeptidyl peptidase IV (DPPIV) ( 3 ) ,a serine protease present on endothelial cells and activated lymphocytes (where it is known as cd26), cleaves Tyr-Pro ( 3 , 4) off of the NPY’s N-terminus, and aminopeptidase P (APP)( 3 ) ,present on vascular smooth-muscle cells (VSMCs), eliminates Tyr (4). The products of these enzyme reactions, C-terminal fragments of NPY devoid of Tyr (4),are no longer able to stimulate vasoconstrictive Y1 receptors but remain active at the Y2 receptors, which are believed to be nonvasoconstrictive. Thus, increased NPY degradation would presumably eliminate the vasoconstrictive activity of the peptide. Vascular responsiveness to NPY is increased not only in stress, but also in other states with elevated plasma catecholamine levels (e.g., in SHR). In endotoxemia, the NPY-mediated responsiveness is not augmented, yet NPY is the only agonist to which vessels do not develop desensitization (1).We hypothesized that high circulating catecholamine levels sensitize blood vessel to NPY. In support of this notion, we have previously found that prolonged exposure of blood vessels to NE markedly upregulates vasopressor responses in vivo and in uitro and augments calcium-stimulatory (CaZ+uptake into cultured VSMC) responses to NPY (1).This effect is long-lasting, resistant to adrenergic and calcium-channel blockers, and dependent on thapsigargin-sensitive intracellular calcium stores, indicating activation by NPY of a unique signaling pathway, distinct from that used by adrenergic agonists (1).The NE-induced sensitization to NPY is mediated by P2-adrenergic (mimicked by isoproterenol) and not al-adrenergic receptors and, in part, is due to stimulation of cyclic adenosine monophosphate. It appears, therefore, that vasoconstrictor hyperresponsiveness to NPY in hyperadrenergic states is due to P-adrenergic “priming” of VSMCs; the exact nature of this cross-talk remains to be established. The efficacy of NPY as a vasoconstrictor would then depend on several factors: the adrenergic status, the activity of NPY degrading enzymes, and the density the Y 1 receptors. Although low adrenergic activity, activation of peptidases, and low Y1 receptor density may eliminate NPY’s vasoconstrictor action, they do not abolish other vasoactive properties of the peptide. We
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Zofia Zukowska-Grojec
(1) have found, and others (4) have confirmed, that NPY stimulates VSMC proliferation independently of serum factors and with an efficacy similar to that of platelet-derived growth factor. The mitogenic effect of NPY is, in part, mimicked by the Y1- and, even more so, the Y2-receptor agonists, products of DPPIV and APP cleavage. Thus, these peptidases do not actually inactivate NPY but convert it to other biologically active forms. Finally, we have found that NPY exerts similar growth-promoting activity on endothelial cells and in vivo stimulates angiogenesis (5). As with the mitogenic effect in VSMCs, the angiogenic action of NPY is, in part, mimicked by Y1 and Y2 agonists (5). Whether this indicates that the growth promoting effects of NPY require cooperation of both receptors or that they are mediated by a novel receptor that recognizes both types of agonists, remains to be determined. Interestingly, the growth-promoting activities of NPY occur at concentrations much lower (< nm) that those required for vasoconstriction (>nM), suggesting that NPY may be foremost the nerve-derived trophic factor, and only at high levels of sympathetic nerve activity is released in large enough quantities to be vasoconstrictive. Thus, physiologically, NPY may be the mediator that regulates blood vessel growth and remodeling during development, the long-suspected sympathetic trophic factor. References 1. Zukowska-Grojec, Z., and Wahlestedt, C. (1993). Origin and actions of neuropeptide Y in the cardiovascular system. In The Biology of Neuropeptide Y and Related Peptides. (W. F. Colmers and C. Wahlestedt, eds.), pp. 315-338. Humana Press, Totowa, New Jersey. 2. Zukowska-Grojec, Z., Dayao, E. K., Karwatowska-Prokopczuk, E., Hauser, G. J., and Doods, H. N. (1996). Stress-induced mesenteric vasoconstriction in rats is mediated by neuropeptide Y Y1 receptors. Am. J. Physiol. , H796-H800. 3. Mentlein, R., Dahms, P., Grandt, D., and Kruger, R. (1993). Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV. Regul. Peptides 49, 133-144. 4. Erlinge, D., Brunkwall, J., and Edvinsson, L. (1994).Neuropeptide Y stimulates proliferation of human vascular smooth muscle cells: Cooperation with noradrenaline and ATP. Regul. Peptides 50, 259-265. 5 . Zukowska-Grojec, Z., Karwatowska-Prokopczuk, E., Yeh, Y-Y., Chen, W-T., Rose, W., and Grant, D. (1995).Endothelial neuropeptide Y (NPY) system and angiogenesis. Circulution 192, 3430.