title: Trpv4 induces collateral vessel growth during regeneration of the arterial circulation.
abstract: The development of a collateral circulation (arteriogenesis), bypassing an arterial occlusion, is important for tissue survival, but it remains functionally defective. Micro array data of growing collateral vessels, exposed to chronically elevated fluid shear stress (FSS), showed increased transcription of the transient receptor potential cation channel, subfamily V, member 4 (Trpv4). Thus, the aim of this study was to investigate the role of the shear stress sensitive Trpv4 in transmitting this physical stimulus into an active growth response. qRT-PCR at different time points during the growth of collateral vessels after femoral artery ligature (FAL) in rats showed a strong positive correlation of Trpv4 transcription and the intensity of FSS. An increased protein expression of Trpv4 was localized in the FSS-sensing endothelium by means of confocal immunohistochemistry. Cultured porcine endothelial cells showed a dose-dependent expression of Trpv4 and an increased level of Ki67-positive cells upon treatment with 4alpha-Phorbol 12,13-didecanoate (4alphaPDD), a specific Trpv4 activator. This was also demonstrated by flow culture experiments. These results were confirmed by in vivo application of 4alphaPDD in rabbit hind limb circulation via an osmotic mini-pump after FAL. Trpv4 expression as well as Ki67-positive staining was significantly increased in collateral vessels. Finally, 4alphaPDD treatment after FAL led to a 61% (215.5 ml/min/mmHg versus 350 ml/min/mmHg) recovery of conductance when compared with the non-occluded artery. Cell culture and in vivo studies demonstrate that an FSS- or a 4alphaPDD-induced activation of Trpv4 leads to an active proliferation of vascular cells and finally triggers collateral growth. Trpv4, a well-known FSS-sensitive vasodilator, has hitherto not been implicated in active growth processes of collateral arteries. This new function may lead to new therapeutic strategies for the treatment of arterial occlusive diseases.
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Troidl
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Troidl
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Wilma
authors.initials: W
authors.lastname: Schierling
authors.affiliation: Xiangsha School of Medicine, Department of Anatomy, Central South University Changsha, Hunan, China.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Cai
authors.affiliation: Kerckhoff Heart Center, Department of Cardiology, Bad Nauheim, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Nef
authors.affiliation: Kerckhoff Heart Center, Department of Cardiology, Bad Nauheim, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Möllmann
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Sava
authors.initials: S
authors.lastname: Kostin
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Schimanski
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Hammer
authors.affiliation: Kerckhoff Heart Center, Department of Cardiology, Bad Nauheim, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Elsässer
authors.affiliation: Division of Vascular and Endovascular Surgery, Goethe-Univ. of Frankfurt/Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmitz-Rixen
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schaper
mesh_terms: D000818:Animals; D001775:Blood Circulation / Q000502:physiology*; D001808:Blood Vessels / Q000254:growth & development* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat