Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes.
Lung Krüppel-like factor (LKLF/KLF2) is an endothelial transcription factor that is crucially involved in murine vasculogenesis and is specifically regulated by flow in vitro. We now show a relation to local flow variations in the adult human vasculature: decreased LKLF expression was noted at the aorta bifurcations to the iliac and carotid arteries, coinciding with neointima formation. The direct involvement of shear stress in the in vivo expression of LKLF was determined independently by in situ hybridization and laser microbeam microdissection/reverse transcriptase-polymerase chain reaction in a murine carotid artery collar model, in which a 4- to 30-fold induction of LKLF occurred at the high-shear sites. Dissection of the biomechanics of LKLF regulation in vitro demonstrated that steady flow and pulsatile flow induced basal LKLF expression 15- and 36-fold at shear stresses greater than approximately 5 dyne/cm2, whereas cyclic stretch had no effect. Prolonged LKLF induction in the absence of flow changed the expression of angiotensin-converting enzyme, endothelin-1, adrenomedullin, and endothelial nitric oxide synthase to levels similar to those observed under prolonged flow. LKLF repression by siRNA suppressed the flow response of endothelin-1, adrenomedullin, and endothelial nitric oxide synthase (P < 0.05). Thus, we demonstrate that endothelial LKLF is regulated by flow in vivo and is a transcriptional regulator of several endothelial genes that control vascular tone in response to flow.
Dekker
Rob J
RJ
Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
van Thienen
Johannes V
JV
Rohlena
Jakub
J
de Jager
Saskia C
SC
Elderkamp
Yvonne W
YW
Seppen
Jurgen
J
de Vries
Carlie J M
CJ
Biessen
Erik A L
EA
van Berkel
Theo J C
TJ
Pannekoek
Hans
H
Horrevoets
Anton J G
AJ
D053607:Adrenomedullin; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D002339:Carotid Arteries / Q000378:metabolism*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors; D007834:Lasers; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010455:Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D011673:Pulsatile Flow; D034741:RNA, Small Interfering / Q000494:pharmacology; D013314:Stress, Mechanical; D015534:Trans-Activators / Q000378:metabolism*
D001057:Apolipoproteins E; D019332:Endothelin-1; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D010455:Peptides; D034741:RNA, Small Interfering; D015534:Trans-Activators; D053607:Adrenomedullin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse