NPY/Y₁ receptor-mediated vasoconstrictory and proliferative effects in pulmonary hypertension.
OBJECTIVE
Pulmonary arteries (PAs) are innervated, but little is known about the role of neuronal axis in pulmonary hypertension (PH). Here, we have examined the role of the neuropeptide Y (NPY) and its Y₁ receptor in PH pathogenesis.


METHODS
NPY was localized by immunofluorescence. Expression of NPY and Y₁ receptor were determined by quantitative PCR. Cellular response to NPY stimulation was assessed by Western blotting, thymidine incorporation and calcium imaging. Wire myography and isolated perfused mouse lung were applied to study pulmonary vasoactive effects of NPY. Selective receptor antagonists were used to assess the contribution of receptor subtypes in mediating NPY effects.


RESULTS
Samples from PH patients showed increased NPYergic innervation within the PA wall and higher Y₁ receptor expression, compared with donors. However, NPY levels were unchanged in both PA and serum. In the chronic hypoxic mouse model, Y₁ receptor were up-regulated, while expression of both NPY and Y₁ receptor was increased in the lungs of monocrotaline and SU5416-hypoxia rats. On a functional level, NPY acutely increased intracellular calcium levels and enhanced vasoconstriction of lung vessels preconstricted with adrenaline. Furthermore, NPY stimulated proliferation of human pulmonary arterial smooth muscle cells and activated p38 and PKD pathways. Correspondingly, higher phosphorylation of PKD was observed in remodelled vessels from PH patients. The selective Y₁ receptor antagonist, BIBO 3304, concentration-dependently inhibited vasoconstrictive and proliferative effects of NPY.


CONCLUSIONS
NPY and Y₁ receptor are possible mediators of both vasoconstriction and pulmonary vascular remodelling in PH.
Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Department of Experimental Anaesthesiology, Medical University of Graz, Graz, Austria.
S
S
Crnkovic
B
B
Egemnazarov
P
P
Jain
U
U
Seay
N
N
Gattinger
L M
LM
Marsh
Z
Z
Bálint
G
G
Kovacs
B
B
Ghanim
W
W
Klepetko
R T
RT
Schermuly
N
N
Weissmann
A
A
Olschewski
G
G
Kwapiszewska
D000328:Adult; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D007211:Indoles; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D055815:Young Adult
D007211:Indoles; D009478:Neuropeptide Y; D011758:Pyrroles; D017476:Receptors, Neuropeptide Y; D014662:Vasoconstrictor Agents; C097212:neuropeptide Y-Y1 receptor; C116890:Semaxinib; D016686:Monocrotaline; D001120:Arginine; C117416:BIBO 3304; D004837:Epinephrine