title: Role of cyclic nucleotide-dependent actin cytoskeletal dynamics:Ca(2+)](i) and force suppression in forskolin-pretreated porcine coronary arteries.
abstract: Initiation of force generation during vascular smooth muscle contraction involves a rise in intracellular calcium ([Ca(2+)]i) and phosphorylation of myosin light chains (MLC). However, reversal of these two processes alone does not account for the force inhibition that occurs during relaxation or inhibition of contraction, implicating that other mechanisms, such as actin cytoskeletal rearrangement, play a role in the suppression of force. In this study, we hypothesize that forskolin-induced force suppression is dependent upon changes in actin cytoskeletal dynamics. To focus on the actin cytoskeletal changes, a physiological model was developed in which forskolin treatment of intact porcine coronary arteries (PCA) prior to treatment with a contractile agonist resulted in complete suppression of force. Pretreatment of PCA with forskolin suppressed histamine-induced force generation but did not abolish [Ca(2+)]i rise or MLC phosphorylation. Additionally, forskolin pretreatment reduced filamentous actin in histamine-treated tissues, and prevented histamine-induced changes in the phosphorylation of the actin-regulatory proteins HSP20, VASP, cofilin, and paxillin. Taken together, these results suggest that forskolin-induced complete force suppression is dependent upon the actin cytoskeletal regulation initiated by the phosphorylation changes of the actin regulatory proteins and not on the MLC dephosphorylation. This model of complete force suppression can be employed to further elucidate the mechanisms responsible for smooth muscle tone, and may offer cues to pathological situations, such as hypertension and vasospasm.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Hocking
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Baudenbacher
authors.forename: Gowthami
authors.initials: G
authors.lastname: Putumbaka
authors.forename: Sneha
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Joyce
authors.initials: J
authors.lastname: Cheung-Flynn
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Brophy
authors.forename: Padmini
authors.initials: P
authors.lastname: Komalavilas
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D050886:HSP20 Heat-Shock Proteins / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D018994:Myosin Light Chains / Q000378:metabolism; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034421:Sus scrofa; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D015815:Cell Adhesion Molecules; D050886:HSP20 Heat-Shock Proteins; D008840:Microfilament Proteins; D018994:Myosin Light Chains; D009712:Nucleotides, Cyclic; D051419:Paxillin; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D005576:Colforsin; D006632:Histamine; D002118:Calcium