Contractility of retinal pericytes grown on silicone elastomer substrates is through a protein kinase A-mediated intracellular pathway in response to vasoactive peptides

Contractility of retinal pericytes grown on silicone elastomer substrates is through a protein kinase A-mediated intracellular pathway in response to vasoactive peptides

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The normal function of retinal capillaries to distribute blood within the retina depends on appropriate contractility of retinal pericytes, which is thought to be modulated by agents that alter intracellular cyclic adenosine-3′-monophosphate (cAMP) levels. We examined the hypothesis that the vasoactive peptides Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase Activating Peptide (PACAP) reduce pericyte contractility via a protein kinase A (PKA)-mediated intracellular pathway that utilises cAMP. We utilised a single-call assay of contractility that is based on visualising the contractile force exerted by the pericytes on a silicone elastomer substrate and quantified, as a contractility index, from the number and length of wrinkles induced in the silicone elastomer by the pericytes. Pericytes were cultured from the retinas of freshly killed abattoir cattle, and identified in culture using immunohistochemical techniques. The pericytes contracted in response to norepinephrine (EC50=8 µM) and relaxed in response to both VIP (EC50=48 nM) and PACAP (EC50=3 nM). The relaxation induced by PACAP was inhibited by Rp-cAMPS (EC50=26 µM), which is an agent that inhibits cAMP binding at PKA. We confirmed the activation of PKA by PACAP in experiments where H89 also inhibited the PACAP-induced relaxation. U71322, which inhibits phospholipase C-linked events, was also able to inhibit the PACAP-induced pericyte relaxation. Our results support the hypothesis that PACAP leads to the relaxation of pericytes via a PKA-mediated intracellular pathway and a phospholipase C-mediated pathway, which probably relies on hyperpolarisation because of activation of Ca2+-dependent potassium channels. This single-cell assay has proved useful as the basis for the development of a diagnostic procedure for diabetic retinopathy, which is an eye disease caused by abnormal regulation of blood flow in the retinal capillaries.


    1. 1)
      • Rouget cells and their function
    2. 2)
      • Retinal vascular patterns VI Mural cells of the retinal capillaries
    3. 3)
      • Differences in contractile function in rat cardiac and skeletal muscle microvasculatures
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    5. 5)
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    9. 9)
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    10. 10)
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    11. 11)
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    12. 12)
      • Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells
    13. 13)
      • Type I receptors for PACAP (a neuropeptide even more important than VIP?)
    14. 14)
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    15. 15)
      • Expression of pituitary adenylate-cyclase-activating polypeptide (PACAP) receptors and PACAP in human fetal retina
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      • Studies on retinal capillary cells in retinal tissue culture
    24. 24)
      • Probing the cyclic nucleotide binding sites of cAMP-dependent protein kinases I and II with analogs of adenosine 3′,5′-cyclic phosphorothioates
    25. 25)
      • Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells
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    27. 27)
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    28. 28)
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    29. 29)
      • On pericytes, particularly their existence on lung capillaries
    30. 30)
      • The fine structure of the terminal vascular bed IV The venules and their perivascular cell (pericytes, adventitial cells)
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    32. 32)
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    33. 33)
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    34. 34)
      • Scanning electron microscopy of pericytes in rat red muscle
    35. 35)
      • Distribution of pituitary adenylate cyclase activating polypeptide mRNA in the developing rat brain
    36. 36)
      • Electron microscopic observation of pituitary adenylate cyclase-activating polypeptide (PACAP)-containing neurons in the rat retina
    37. 37)
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    38. 38)
      • Effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on cyclic AMP formation in duck and goose brain
    39. 39)
      • Functional and molecular expression of PACAP/VIP receptors in the rat retina
    40. 40)
      • The inhibitor protein of the cAMP-dependent protein kinase-catalytic subunit interaction. Parameters of complex formation
    41. 41)
      • PACAP activates PKA, PKC and Ca2+ signaling cascades in rat neuroepithelial cells
    42. 42)
      • K+ channels in cultured bovine retinal pericytes: effects of beta-adrenergic stimulation
    43. 43)
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    44. 44)
      • PGI2 open potassium channels in retinal pericytes by cyclic AMP-stimulated, cross-activation of PKG

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