PMID- 32483447
OWN - NLM
STAT- MEDLINE
DCOM- 20210518
LR  - 20210518
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 10
IP  - 14
DP  - 2020
TI  - Kindlin-2 deficiency induces fatal intestinal obstruction in mice.
PG  - 6182-6200
LID - 10.7150/thno.46553 [doi]
AB  - Rationale: Smooth muscle-motility disorders are mainly characterized by impaired 
      contractility and functional intestinal obstruction. Some of these cases are 
      caused by genetic mutations of smooth muscle genes ACTA2, ACTG2, MYH11, MYLK and 
      LMOD1. Still the etiology is complex and multifactorial and the underlying 
      pathology is poorly understood. Integrin interaction protein Kindlin-2 is widely 
      expressed in striated and smooth muscle cells (SMC). However, the function of 
      Kindlin-2 in the smooth muscle remains elusive. Methods: We generated two mouse 
      models using different cre promoter transgenic mice, Kindlin-2(fl/fl) SM22alpha-cre+ 
      (cKO mice) and Kindlin-2(fl/fl); MYH-cre+ (iKO mice). Embryos and adult tissues 
      were prepared for hematoxylin and eosin (H&E) staining, immunohistochemistry 
      (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) 
      apoptosis assay. We investigated ultrastructure changes of mouse smooth muscle 
      using transmission electron microscopy (TEM) and measured smooth muscle 
      contractile force in mounting aortic and intestinal rings using the multiwire 
      myograph system (DMT 620M). In addition, cell traction force microscopy (CTFM) 
      was applied to observe the functional change of primary SMC after Kindlin-2 
      depletion by RNAi. Results: Depletion of Kindlin-2 encoding gene Fermt2 in 
      embryonic smooth muscles leads to apoptosis, downregulates the key components of 
      SMC, impairs smooth muscle development, and finally causes embryonic death at 
      E14.5. Tamoxifen-induced Kindlin-2-specific knockout in adult mouse smooth muscle 
      showed decreased blood pressure, intestinal hypoperistalsis, and eventually died 
      of intestinal obstruction. Kindlin-2 depletion also leads to downregulated Myh11, 
      alpha-SMA, and CNN, shortened myofilament, broken myofibrils, and impaired 
      contractility of the smooth muscles in iKO mice. Mechanistically, loss of 
      Kindlin-2 decreases Ca2(+) influx in primary vascular smooth muscle cells (PVSMC) 
      by downregulating the expression of calcium-binding protein S100A14 and STIM1. 
      Conclusion: We demonstrated that Kindlin-2 is essential for maintaining the 
      normal structure and function of smooth muscles. Loss of Kindlin-2 impairs smooth 
      muscle formation during embryonic development by inducing apoptosis and 
      jeopardizes the contraction of adult smooth muscle by blocking Ca(2+) influx that 
      leads to intestinal obstruction. Mice with Kindlin-2 depletion in adult smooth 
      muscle could be a potent animal model of intestinal obstruction for disease 
      research, drug treatment and prognosis.
CI  - (c) The author(s).
FAU - He, Xiaokun
AU  - He X
AD  - Department of Human Anatomy, Histology and Embryology, Key Laboratory of 
      Carcinogenesis and Translational Research, Ministry of Education, and State Key 
      Laboratory of Natural and Biomimetic Drugs, Peking University Health Science 
      Center, Beijing 100191, China.
FAU - Song, Jiagui
AU  - Song J
AD  - Department of Human Anatomy, Histology and Embryology, Key Laboratory of 
      Carcinogenesis and Translational Research, Ministry of Education, and State Key 
      Laboratory of Natural and Biomimetic Drugs, Peking University Health Science 
      Center, Beijing 100191, China.
FAU - Cai, Zeyu
AU  - Cai Z
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Beijing 100191, China.
FAU - Chi, Xiaochun
AU  - Chi X
AD  - Department of Human Anatomy, Histology and Embryology, Key Laboratory of 
      Carcinogenesis and Translational Research, Ministry of Education, and State Key 
      Laboratory of Natural and Biomimetic Drugs, Peking University Health Science 
      Center, Beijing 100191, China.
FAU - Wang, Zhenbin
AU  - Wang Z
AD  - Department of Human Anatomy, Histology and Embryology, Key Laboratory of 
      Carcinogenesis and Translational Research, Ministry of Education, and State Key 
      Laboratory of Natural and Biomimetic Drugs, Peking University Health Science 
      Center, Beijing 100191, China.
FAU - Yang, Decao
AU  - Yang D
AD  - Department of Human Anatomy, Histology and Embryology, Key Laboratory of 
      Carcinogenesis and Translational Research, Ministry of Education, and State Key 
      Laboratory of Natural and Biomimetic Drugs, Peking University Health Science 
      Center, Beijing 100191, China.
FAU - Xie, Sian
AU  - Xie S
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Beijing 100191, China.
FAU - Zhou, Jing
AU  - Zhou J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Beijing 100191, China.
FAU - Fu, Yi
AU  - Fu Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Beijing 100191, China.
FAU - Li, Wei
AU  - Li W
AD  - Department of Surgery and Interdepartmental Program in Vascular Biology and 
      Therapeutics, Yale University School of Medicine, New Haven, Connecticut, USA.
FAU - Kong, Wei
AU  - Kong W
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Beijing 100191, China.
FAU - Zhan, Jun
AU  - Zhan J
AD  - Department of Human Anatomy, Histology and Embryology, Key Laboratory of 
      Carcinogenesis and Translational Research, Ministry of Education, and State Key 
      Laboratory of Natural and Biomimetic Drugs, Peking University Health Science 
      Center, Beijing 100191, China.
FAU - Zhang, Hongquan
AU  - Zhang H
AD  - Department of Human Anatomy, Histology and Embryology, Key Laboratory of 
      Carcinogenesis and Translational Research, Ministry of Education, and State Key 
      Laboratory of Natural and Biomimetic Drugs, Peking University Health Science 
      Center, Beijing 100191, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200515
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Cytoskeletal Proteins)
RN  - 0 (Muscle Proteins)
RN  - 0 (kindlin-2 protein, mouse)
SB  - IM
MH  - Animals
MH  - Calcium-Binding Proteins/*metabolism
MH  - Cell Movement
MH  - Cytoskeletal Proteins/*deficiency/genetics
MH  - Disease Models, Animal
MH  - Intestinal Obstruction/etiology/metabolism/*pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Muscle Contraction
MH  - Muscle Proteins/*deficiency/genetics
MH  - Muscle, Smooth/metabolism/*pathology
PMC - PMC7255029
OTO - NOTNLM
OT  - Intestinal obstruction
OT  - Kindlin-2
OT  - Smooth muscle contraction
OT  - Smooth muscle structure
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2020/06/03 06:00
MHDA- 2021/05/19 06:00
PMCR- 2020/01/01
CRDT- 2020/06/03 06:00
PHST- 2020/04/01 00:00 [received]
PHST- 2020/04/22 00:00 [accepted]
PHST- 2020/06/03 06:00 [entrez]
PHST- 2020/06/03 06:00 [pubmed]
PHST- 2021/05/19 06:00 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - thnov10p6182 [pii]
AID - 10.7150/thno.46553 [doi]
PST - epublish
SO  - Theranostics. 2020 May 15;10(14):6182-6200. doi: 10.7150/thno.46553. eCollection 
      2020.