TY - JOUR
T1 - Higher gestational weight gain delays wound healing and reduces expression of long non-coding RNA KLRK1-AS1 in neonatal endothelial progenitor cells
AU - Weiss, Elisa
AU - Schrüfer, Anna
AU - Tocantins, Carolina
AU - Diniz, Mariana Simoes
AU - Novakovic, Boris
AU - van Bergen, Anke S.
AU - Kulovic-Sissawo, Azra
AU - Saffery, Richard
AU - Boon, Reinier A.
AU - Hiden, Ursula
N1 - Funding Information: E.W. was supported by the Austrian Science Fund FWF (DOC 31-B26) and the Medical University of Graz, Austria, through the PhD Program Inflammatory Disorders in Pregnancy (DP-iDP). E.W. and A.K.S. were financed by the FWF project KLI 1023 (to U.H.). C.T. and M.S.D. were funded by the Portuguese Foundation for Science and Technology under the FCT-doctoral Fellowships: C.T., SFRH/BD/11924/2022; M.S.D., SFRH/BD/11934/2022. The authors thank Bettina Amtmann and Petra Winkler for collection of umbilical cord blood. Funding Information: E.W. was supported by the Austrian Science Fund FWF (DOC 31‐B26) and the Medical University of Graz, Austria, through the PhD Program Inflammatory Disorders in Pregnancy (DP‐iDP). E.W. and A.K.S. were financed by the FWF project KLI 1023 (to U.H.). C.T. and M.S.D. were funded by the Portuguese Foundation for Science and Technology under the FCT‐doctoral Fellowships: C.T., SFRH/BD/11924/2022; M.S.D., SFRH/BD/11934/2022. Publisher Copyright: © 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - Abstract: High gestational weight gain (GWG) is a cardiovascular risk factor and may disturb neonatal endothelial function. Long non-coding RNAs (lncRNAs) regulate gene expression epigenetically and can modulate endothelial function. Endothelial colony forming cells (ECFCs), circulating endothelial precursors, are a recruitable source of endothelial cells and sustain endothelial function, vascular growth and repair. We here investigated whether higher GWG affects neonatal ECFC function and elucidated the role of lncRNAs herein. Wound healing of umbilical cord blood-derived ECFCs after pregnancies with GWG <13 kg versus >13 kg was determined in a scratch assay and based on monolayer impedance after electric wounding (electric cell-substrate impedance sensing, ECIS). LncRNA expression was analysed by RNA sequencing. The function of killer cell lectin-like receptor K1 antisense RNA (KLRK1-AS1) was investigated after siRNA-based knockdown. Closure of the scratch was delayed by 25% (P = 0.041) in the higher GWG group and correlated inversely with GWG (R = −0.538, P = 0.012) in all subjects (n = 22). Similarly, recovery of the monolayer barrier after electric wounding was delayed (−11% after 20 h; P = 0.014; n = 15). Several lncRNAs correlated with maternal GWG, the most significant one being KLRK1-AS1 (log2 fold change = −0.135, P < 0.001, n = 35). KLRK1-AS1 knockdown (n = 4) reduced barrier recovery after electric wounding by 21% (P = 0.029) and KLRK1-AS1 expression correlated with the time required for wound healing for both scratch (R = 0.447, P = 0.033) and impedance-based assay (R = 0.629, P = 0.014). Higher GWG reduces wound healing of neonatal ECFCs, and lower levels of the lncRNA KLRK1-AS1 may underlie this. (Figure presented.). Key points: Maternal cardiovascular risk factors such as diabetes, obesity and smoking in pregnancy disturb fetal endothelial function, and we here investigated whether also high gestational weight gain (GWG) has an impact on fetal endothelial cells. Circulating endothelial progenitor cells (endothelial colony forming cells, ECFCs) are highly abundant in the neonatal blood stream and serve as a circulating pool for vascular growth and repair. We revealed that higher GWG delays wound healing capacity of ECFCs in vitro. We identified the regulatory RNA lncRNA KLRK1-AS1 as a link between GWG and delayed ECFC wound healing. Our data show that high GWG, independent of pre-pregnancy BMI, affects neonatal ECFC function.
AB - Abstract: High gestational weight gain (GWG) is a cardiovascular risk factor and may disturb neonatal endothelial function. Long non-coding RNAs (lncRNAs) regulate gene expression epigenetically and can modulate endothelial function. Endothelial colony forming cells (ECFCs), circulating endothelial precursors, are a recruitable source of endothelial cells and sustain endothelial function, vascular growth and repair. We here investigated whether higher GWG affects neonatal ECFC function and elucidated the role of lncRNAs herein. Wound healing of umbilical cord blood-derived ECFCs after pregnancies with GWG <13 kg versus >13 kg was determined in a scratch assay and based on monolayer impedance after electric wounding (electric cell-substrate impedance sensing, ECIS). LncRNA expression was analysed by RNA sequencing. The function of killer cell lectin-like receptor K1 antisense RNA (KLRK1-AS1) was investigated after siRNA-based knockdown. Closure of the scratch was delayed by 25% (P = 0.041) in the higher GWG group and correlated inversely with GWG (R = −0.538, P = 0.012) in all subjects (n = 22). Similarly, recovery of the monolayer barrier after electric wounding was delayed (−11% after 20 h; P = 0.014; n = 15). Several lncRNAs correlated with maternal GWG, the most significant one being KLRK1-AS1 (log2 fold change = −0.135, P < 0.001, n = 35). KLRK1-AS1 knockdown (n = 4) reduced barrier recovery after electric wounding by 21% (P = 0.029) and KLRK1-AS1 expression correlated with the time required for wound healing for both scratch (R = 0.447, P = 0.033) and impedance-based assay (R = 0.629, P = 0.014). Higher GWG reduces wound healing of neonatal ECFCs, and lower levels of the lncRNA KLRK1-AS1 may underlie this. (Figure presented.). Key points: Maternal cardiovascular risk factors such as diabetes, obesity and smoking in pregnancy disturb fetal endothelial function, and we here investigated whether also high gestational weight gain (GWG) has an impact on fetal endothelial cells. Circulating endothelial progenitor cells (endothelial colony forming cells, ECFCs) are highly abundant in the neonatal blood stream and serve as a circulating pool for vascular growth and repair. We revealed that higher GWG delays wound healing capacity of ECFCs in vitro. We identified the regulatory RNA lncRNA KLRK1-AS1 as a link between GWG and delayed ECFC wound healing. Our data show that high GWG, independent of pre-pregnancy BMI, affects neonatal ECFC function.
KW - endothelial colony forming cells (ECFC)
KW - fetal programming
KW - gestational weight gain
KW - lncRNA (long non-coding RNA)
KW - wound healing
UR - http://www.scopus.com/inward/record.url?scp=85165432595&partnerID=8YFLogxK
U2 - https://doi.org/10.1113/JP284871
DO - https://doi.org/10.1113/JP284871
M3 - Article
C2 - 37470310
SN - 0022-3751
VL - 601
SP - 3961
EP - 3974
JO - Journal of physiology
JF - Journal of physiology
IS - 17
ER -