TY - JOUR
T1 - Novel regulatory roles of small leucine-rich proteoglycans in remodeling of the uterine cervix in pregnancy
AU - Colon-Caraballo, Mariano
AU - Lee, Nicole
AU - Nallasamy, Shanmugasundaram
AU - Myers, Kristin
AU - Hudson, David
AU - Iozzo, Renato V.
AU - Mahendroo, Mala
N1 - Funding Information:
This work was supported by the National Institutes of Health Grant R01 HD088481 (to MM and KM), National Science Foundation 1454412 (to KM) and Eunice Kennedy Shriver National Intitute of Child Health & Human Development of the National Intitutes of Health F32HD103314 (to MCC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This work was supported by the National Institutes of Health Grant R01 HD088481 (to MM and KM), National Science Foundation 1454412 (to KM) and Eunice Kennedy Shriver National Intitute of Child Health & Human Development of the National Intitutes of Health F32HD103314 (to MCC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.We thank Dr. Marian Young for providing the Bgn−/− mice and Dr. Shukti Chakravarti for providing the Lum−/− mice. Authors would like to thank Shivani Bhatnagar for technical support in the lumican western blot and Marilyn Archer for collagen cross-link measurements. We thank Dr. Larry Fisher at the National Institutes of Health National Institute of Dental and Craniofacial Research and Skeletal Disease Branch for providing the biglycan antibody (LF-107). We acknowledge the assistance of the UT Southwestern Electron Microscopy Core and the Live Cell Imaging Core supported by the NIH grant 1S10OD021684–01. We thank Dr. Katherine Luby-Phelps for critical input and assistance for the measurement of collagen fibril diameter and spacing.
Funding Information:
We thank Dr. Marian Young for providing the Bgn −/− mice and Dr. Shukti Chakravarti for providing the Lum −/− mice. Authors would like to thank Shivani Bhatnagar for technical support in the lumican western blot and Marilyn Archer for collagen cross-link measurements. We thank Dr. Larry Fisher at the National Institutes of Health National Institute of Dental and Craniofacial Research and Skeletal Disease Branch for providing the biglycan antibody (LF-107). We acknowledge the assistance of the UT Southwestern Electron Microscopy Core and the Live Cell Imaging Core supported by the NIH grant 1S10OD021684 – 01 . We thank Dr. Katherine Luby-Phelps for critical input and assistance for the measurement of collagen fibril diameter and spacing.
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2022/1
Y1 - 2022/1
N2 - The cervix undergoes rapid and dramatic shifts in collagen and elastic fiber structure to achieve its disparate physiological roles of competence during pregnancy and compliance during birth. An understanding of the structure-function relationships of collagen and elastic fibers to maintain extracellular matrix (ECM) homeostasis requires an understanding of the mechanisms executed by non-structural ECM molecules. Small-leucine rich proteoglycans (SLRPs) play key functions in biology by affecting collagen fibrillogenesis and regulating enzyme and growth factor bioactivities. In the current study, we evaluated collagen and elastic fiber structure-function relationships in mouse cervices using mice with genetic ablation of decorin and/or biglycan genes as representative of Class I SLRPs, and lumican gene representative of Class II SLRP. We identified structural defects in collagen fibril and elastic fiber organization in nonpregnant mice lacking decorin, or biglycan or lumican with variable resolution of defects noted during pregnancy. The severity of collagen and elastic fiber defects was greater in nonpregnant mice lacking both decorin and biglycan and defects were maintained throughout pregnancy. Loss of biglycan alone reduced tissue extensibility in nonpregnant mice while loss of both decorin and biglycan manifested in decreased rupture stretch in late pregnancy. Collagen cross-link density was similar in the Class I SLRP null mice as compared to wild-type nonpregnant and pregnant controls. A broader range in collagen fibril diameter along with an increase in mean fibril spacing was observed in the mutant mice compared to wild-type controls. Collectively, these findings uncover functional redundancy and hierarchical roles of Class I and Class II SLRPs as key regulators of cervical ECM remodeling in pregnancy. These results expand our understating of the critical role SLRPs play to maintain ECM homeostasis in the cervix.
AB - The cervix undergoes rapid and dramatic shifts in collagen and elastic fiber structure to achieve its disparate physiological roles of competence during pregnancy and compliance during birth. An understanding of the structure-function relationships of collagen and elastic fibers to maintain extracellular matrix (ECM) homeostasis requires an understanding of the mechanisms executed by non-structural ECM molecules. Small-leucine rich proteoglycans (SLRPs) play key functions in biology by affecting collagen fibrillogenesis and regulating enzyme and growth factor bioactivities. In the current study, we evaluated collagen and elastic fiber structure-function relationships in mouse cervices using mice with genetic ablation of decorin and/or biglycan genes as representative of Class I SLRPs, and lumican gene representative of Class II SLRP. We identified structural defects in collagen fibril and elastic fiber organization in nonpregnant mice lacking decorin, or biglycan or lumican with variable resolution of defects noted during pregnancy. The severity of collagen and elastic fiber defects was greater in nonpregnant mice lacking both decorin and biglycan and defects were maintained throughout pregnancy. Loss of biglycan alone reduced tissue extensibility in nonpregnant mice while loss of both decorin and biglycan manifested in decreased rupture stretch in late pregnancy. Collagen cross-link density was similar in the Class I SLRP null mice as compared to wild-type nonpregnant and pregnant controls. A broader range in collagen fibril diameter along with an increase in mean fibril spacing was observed in the mutant mice compared to wild-type controls. Collectively, these findings uncover functional redundancy and hierarchical roles of Class I and Class II SLRPs as key regulators of cervical ECM remodeling in pregnancy. These results expand our understating of the critical role SLRPs play to maintain ECM homeostasis in the cervix.
KW - Bgn= biglycan
KW - Biomechanics
KW - Cervix
KW - Collagen
KW - D12= gestational day 12
KW - D15= gestational day 15
KW - D18= gestational day 18
KW - D6= gestational day 6
KW - DKO= double knockout
KW - Dcn= decorin
KW - ECM= extracellular matrix
KW - EDS= Ehler-Danlos syndrome
KW - Elastic fibers
KW - Fmod= fibromodulin
KW - HP= hydroxylysylpyridinolines cross-links
KW - LP= lysylpyridinolines cross-links
KW - Lum= lumican
KW - MS= midstroma
KW - Myo= myometrial tissue
KW - NP= non pregnant
KW - PPROM= preterm premature rupture of fetal membranes
KW - PTB= preterm birth
KW - Pregnancy
KW - Proteoglycan
KW - SE= subepithelia
KW - SHG= second harmonic generation imaging
KW - SLRPs= small leucine rich proteoglycans
KW - TEM= tissue electron microscopy
KW - WT= wild-type
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U2 - 10.1016/j.matbio.2021.11.004
DO - 10.1016/j.matbio.2021.11.004
M3 - Article
C2 - 34863915
AN - SCOPUS:85121230900
SN - 0945-053X
VL - 105
SP - 53
EP - 71
JO - Matrix Biology
JF - Matrix Biology
ER -