Prdm16 Supports Arterial Flow Recovery by Maintaining Endothelial Function
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Prdm16 Supports Arterial Flow Recovery by Maintaining Endothelial Function. / Craps, Sander; Van Wauwe, Jore; De Moudt, Sofie; De Munck, Dorien; Leloup, Arthur J A; Boeckx, Bram; Vervliet, Tim; Dheedene, Wouter; Criem, Nathan; Geeroms, Carla; Jones, Elizabeth A V; Zwijsen, An; Lambrechts, Diether; Fransen, Paul; Beerens, Manu; Luttun, Aernout.
in: CIRC RES, Jahrgang 129, Nr. 1, 25.06.2021, S. 63-77.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Prdm16 Supports Arterial Flow Recovery by Maintaining Endothelial Function
AU - Craps, Sander
AU - Van Wauwe, Jore
AU - De Moudt, Sofie
AU - De Munck, Dorien
AU - Leloup, Arthur J A
AU - Boeckx, Bram
AU - Vervliet, Tim
AU - Dheedene, Wouter
AU - Criem, Nathan
AU - Geeroms, Carla
AU - Jones, Elizabeth A V
AU - Zwijsen, An
AU - Lambrechts, Diether
AU - Fransen, Paul
AU - Beerens, Manu
AU - Luttun, Aernout
PY - 2021/6/25
Y1 - 2021/6/25
N2 - Rationale:Understanding the mechanisms that regulate arterial flow recovery is important to design treatment options for peripheral artery disease patients ineligible for invasive revascularization. Transcriptional orchestrators of this recovery process represent an appealing target for treatment design. We previously identified Prdm (positive regulatory domain-containing protein) 16 as an arterial-specific endothelial transcription factor but its in vivo role in arteries remains completely unknown.Objective:To unravel the role of Prdm16 in arteries under physiological and pathological conditions, more specifically during peripheral artery disease.Methods and Results:Within the vasculature, Prdm16 expression was strictly confined to arterial endothelial and smooth muscle cells. Heterozygous loss of Prdm16 caused a modest reduction of the inner arterial diameter and smooth muscle cell coating without compromising vasomotor function. Upon femoral artery ligation, Prdm16+/− mice featured significantly impaired flow recovery to ischemic limbs. This impairment was recapitulated in mice with a Prdm16 deletion specifically in endothelial cells (EC-Prdm16−/−) but not smooth muscle cells. Structural collateral remodeling was normal in both Prdm16+/− and EC-Prdm16−/− mice, but significant endothelial dysfunction postligation was present in EC-Prdm16−/− mice as evidenced by impaired endothelial-dependent relaxation. Upon ligation, endothelial Prdm16 deficiency altered the expression of genes encoding endothelial cell function regulators, many related to nitric oxide bioavailability and Ca2+ homeostasis. Accordingly, Prdm16 overexpression in cultured endothelial cells affected both total cellular Ca2+ levels and store-operated Ca2+ entry.Conclusions:We showed that Prdm16 is indispensable for arterial flow recovery under pathological challenge not because it affects structural remodeling but due to its role in maintaining endothelial function. It, therefore, represents an appealing target for designing novel therapeutic strategies for no-option patients with peripheral artery disease.
AB - Rationale:Understanding the mechanisms that regulate arterial flow recovery is important to design treatment options for peripheral artery disease patients ineligible for invasive revascularization. Transcriptional orchestrators of this recovery process represent an appealing target for treatment design. We previously identified Prdm (positive regulatory domain-containing protein) 16 as an arterial-specific endothelial transcription factor but its in vivo role in arteries remains completely unknown.Objective:To unravel the role of Prdm16 in arteries under physiological and pathological conditions, more specifically during peripheral artery disease.Methods and Results:Within the vasculature, Prdm16 expression was strictly confined to arterial endothelial and smooth muscle cells. Heterozygous loss of Prdm16 caused a modest reduction of the inner arterial diameter and smooth muscle cell coating without compromising vasomotor function. Upon femoral artery ligation, Prdm16+/− mice featured significantly impaired flow recovery to ischemic limbs. This impairment was recapitulated in mice with a Prdm16 deletion specifically in endothelial cells (EC-Prdm16−/−) but not smooth muscle cells. Structural collateral remodeling was normal in both Prdm16+/− and EC-Prdm16−/− mice, but significant endothelial dysfunction postligation was present in EC-Prdm16−/− mice as evidenced by impaired endothelial-dependent relaxation. Upon ligation, endothelial Prdm16 deficiency altered the expression of genes encoding endothelial cell function regulators, many related to nitric oxide bioavailability and Ca2+ homeostasis. Accordingly, Prdm16 overexpression in cultured endothelial cells affected both total cellular Ca2+ levels and store-operated Ca2+ entry.Conclusions:We showed that Prdm16 is indispensable for arterial flow recovery under pathological challenge not because it affects structural remodeling but due to its role in maintaining endothelial function. It, therefore, represents an appealing target for designing novel therapeutic strategies for no-option patients with peripheral artery disease.
KW - Animals
KW - Aorta/metabolism
KW - Calcium/metabolism
KW - Calcium Signaling
KW - Cells, Cultured
KW - Collateral Circulation
KW - DNA-Binding Proteins/genetics
KW - Disease Models, Animal
KW - Endothelial Cells/metabolism
KW - Endothelium, Vascular/metabolism
KW - Femoral Artery/metabolism
KW - Hindlimb/blood supply
KW - Ischemia/genetics
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Muscle, Smooth, Vascular/metabolism
KW - Myocytes, Smooth Muscle/metabolism
KW - Neovascularization, Physiologic
KW - Regional Blood Flow
KW - Transcription Factors/genetics
U2 - 10.1161/CIRCRESAHA.120.318501
DO - 10.1161/CIRCRESAHA.120.318501
M3 - SCORING: Journal article
C2 - 33902304
VL - 129
SP - 63
EP - 77
JO - CIRC RES
JF - CIRC RES
SN - 0009-7330
IS - 1
ER -