PMID- 37838010
OWN - NLM
STAT- MEDLINE
DCOM- 20240325
LR  - 20240406
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 194
IP  - 4
DP  - 2024 Apr
TI  - Defining the Functional Influence of Endothelial Cell-Expressed Oncogenic 
      Activating Mutations on Vascular Morphogenesis and Capillary Assembly.
PG  - 574-598
LID - S0002-9440(23)00375-9 [pii]
LID - 10.1016/j.ajpath.2023.08.017 [doi]
AB  - This study sought to define key molecules and signals controlling major steps in 
      vascular morphogenesis, and how these signals regulate pericyte recruitment and 
      pericyte-induced basement membrane deposition. The morphogenic impact of 
      endothelial cell (EC) expression of activating mutants of Kirsten rat sarcoma 
      virus (kRas), mitogen-activated protein kinase 1 (Mek1), 
      phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), 
      Akt serine/threonine kinase 1 (Akt1), Ras homolog enriched in brain (Rheb) Janus 
      kinase 2 (Jak2), or signal transducer and activator of transcription 3 (Stat3) 
      expression versus controls was evaluated, along with EC signaling events, 
      pharmacologic inhibitor assays, and siRNA suppression experiments. Primary 
      stimulators of EC lumen formation included kRas, Akt1, and Mek1, whereas PIK3CA 
      and Akt1 stimulated a specialized type of cystic lumen formation. In contrast, 
      the key drivers of EC sprouting behavior were Jak2, Stat3, Mek1, PIK3CA, and 
      mammalian target of rapamycin (mTor). These conclusions are further supported by 
      pharmacologic inhibitor and siRNA suppression experiments. EC expression of 
      active Akt1, kRas, and PIK3CA led to markedly dysregulated lumen formation 
      coupled to strongly inhibited pericyte recruitment and basement membrane 
      deposition. For example, activated Akt1 expression in ECs excessively stimulated 
      lumen formation, decreased EC sprouting behavior, and showed minimal pericyte 
      recruitment with reduced mRNA expression of platelet-derived growth factor-BB, 
      platelet-derived growth factor-DD, and endothelin-1, critical EC-derived factors 
      known to stimulate pericyte invasion. The study identified key signals 
      controlling fundamental steps in capillary morphogenesis and maturation and 
      provided mechanistic details on why EC activating mutations induced a capillary 
      deficiency state with abnormal lumens, impaired pericyte recruitment, and 
      basement deposition: predisposing stimuli for the development of vascular 
      malformations.
CI  - Copyright (c) 2024 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Lin, Prisca K
AU  - Lin PK
AD  - Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, 
      University of South Florida School of Medicine, Tampa, Florida.
FAU - Sun, Zheying
AU  - Sun Z
AD  - Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, 
      University of South Florida School of Medicine, Tampa, Florida.
FAU - Davis, George E
AU  - Davis GE
AD  - Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, 
      University of South Florida School of Medicine, Tampa, Florida. Electronic 
      address: gedavis@usf.edu.
LA  - eng
PT  - Journal Article
DEP - 20231012
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - *Proto-Oncogene Proteins p21(ras)/genetics
MH  - *Endothelial Cells/metabolism
MH  - Morphogenesis/genetics
MH  - Platelet-Derived Growth Factor/metabolism
MH  - Mutation
MH  - RNA, Small Interfering/metabolism
MH  - Class I Phosphatidylinositol 3-Kinases/metabolism
PMC - PMC10988768
EDAT- 2023/10/15 05:46
MHDA- 2024/03/25 06:43
PMCR- 2025/04/01
CRDT- 2023/10/14 19:24
PHST- 2023/06/22 00:00 [received]
PHST- 2023/08/02 00:00 [revised]
PHST- 2023/08/15 00:00 [accepted]
PHST- 2025/04/01 00:00 [pmc-release]
PHST- 2024/03/25 06:43 [medline]
PHST- 2023/10/15 05:46 [pubmed]
PHST- 2023/10/14 19:24 [entrez]
AID - S0002-9440(23)00375-9 [pii]
AID - 10.1016/j.ajpath.2023.08.017 [doi]
PST - ppublish
SO  - Am J Pathol. 2024 Apr;194(4):574-598. doi: 10.1016/j.ajpath.2023.08.017. Epub 
      2023 Oct 12.