PMID- 37278410
OWN - NLM
STAT- MEDLINE
DCOM- 20230714
LR  - 20230804
IS  - 1522-1504 (Electronic)
IS  - 1040-0605 (Print)
IS  - 1040-0605 (Linking)
VI  - 325
IP  - 2
DP  - 2023 Aug 1
TI  - Intrapulmonary arterial contraction assay reveals region-specific deregulation of 
      vasoreactivity to lung injuries.
PG  - L114-L124
LID - 10.1152/ajplung.00293.2022 [doi]
AB  - Intrapulmonary arteries located in the proximal lung differ from those in the 
      distal lung in size, cellular composition, and the surrounding microenvironment. 
      However, whether these structural variations lead to region-specific regulation 
      of vasoreactivity in homeostasis and following injury is unknown. Herein, we 
      employ a two-step method of precision-cut lung slice (PCLS) preparation, which 
      maintains almost intact intrapulmonary arteries, to assess contractile and 
      relaxation responses of proximal preacinar arteries (PaAs) and distal intraacinar 
      arteries (IaAs) in mice. We found that PaAs exhibited robust vasoconstriction in 
      response to contractile agonists and significant nitric oxide (NO)-induced 
      vasodilation. In comparison, IaAs were less contractile and displayed a greater 
      relaxation response to NO. Furthermore, in a mouse model of pulmonary arterial 
      hypertension (PAH) induced by chronic exposure to ovalbumin (OVA) allergen and 
      hypoxia (OVA-HX), IaAs demonstrated a reduced vasocontraction despite vascular 
      wall thickening with the emergence of new alphaSMA(+) cells coexpressing markers of 
      pericytes. In contrast, PaAs became hypercontractile and less responsive to NO. 
      The reduction in relaxation of PaAs was associated with decreased expression of 
      protein kinase G, a key component of the NO pathway, following chronic OVA-HX 
      exposure. Taken together, the PCLS prepared using the modified preparation method 
      enables functional evaluation of pulmonary arteries in different anatomical 
      locations and reveals region-specific mechanisms underlying the pathophysiology 
      of PAH in a mouse model.NEW & NOTEWORTHY Utilizing mouse precision-cut lung 
      slices with preserved intrapulmonary vessels, we demonstrated a 
      location-dependent structural and contractile regulation of pulmonary arteries in 
      health and on noxious stimulations. For instance, chronic ovalbumin and hypoxic 
      exposure increased pulmonary arterial pressure (PAH) by remodeling intraacinar 
      arterioles to reduce vascular wall compliance while enhancing vasoconstriction in 
      proximal preacinar arteries. These findings suggest region-specific mechanisms 
      and therapeutic targets for pulmonary vascular diseases such as PAH.
FAU - Bai, Yan
AU  - Bai Y
AUID- ORCID: 0000-0002-8393-3062
AD  - Division of Neonatology and Newborn Medicine, Department of Pediatrics, 
      Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 
      United States.
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United 
      States.
FAU - Li, Guang
AU  - Li G
AD  - Department of Critical Care Medicine, Renmin Hospital and Wuhan University, 
      Wuhan, People's Republic of China.
FAU - Yung, Laiming
AU  - Yung L
AD  - Cardiovascular Research Center, Division of Cardiovascular Medicine, Department 
      of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 
      Massachusetts, United States.
FAU - Yu, Paul B
AU  - Yu PB
AD  - Cardiovascular Research Center, Division of Cardiovascular Medicine, Department 
      of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, 
      Massachusetts, United States.
FAU - Ai, Xingbin
AU  - Ai X
AD  - Division of Neonatology and Newborn Medicine, Department of Pediatrics, 
      Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 
      United States.
LA  - eng
GR  - K08 HL135443/HL/NHLBI NIH HHS/United States
GR  - R01 HL132991/HL/NHLBI NIH HHS/United States
GR  - R01 HL159443/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230606
PL  - United States
TA  - Am J Physiol Lung Cell Mol Physiol
JT  - American journal of physiology. Lung cellular and molecular physiology
JID - 100901229
RN  - 9006-59-1 (Ovalbumin)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Lung Injury/metabolism
MH  - Ovalbumin
MH  - Lung/metabolism
MH  - Pulmonary Artery/metabolism
MH  - Vasodilation/physiology
MH  - Vasoconstriction/physiology
MH  - Nitric Oxide/metabolism
MH  - Hypoxia/metabolism
PMC - PMC10393320
OTO - NOTNLM
OT  - hypoxia
OT  - precision-cut lung slice
OT  - pulmonary arterial smooth muscle cell
OT  - pulmonary artery
OT  - pulmonary hypertension
COIS- P.B.Y. is a founder and stockholder of Keros Therapeutics. P.B.Y. has received 
      research support from Pfizer Inc., Regeneron Therapeutics, Inozyme 
      Pharmaceutical, and Gossamer Bio Inc. None of the other authors has any conflicts 
      of interest, financial or otherwise, to disclose.
EDAT- 2023/06/06 13:09
MHDA- 2023/07/14 13:06
PMCR- 2024/08/01
CRDT- 2023/06/06 08:03
PHST- 2024/08/01 00:00 [pmc-release]
PHST- 2023/07/14 13:06 [medline]
PHST- 2023/06/06 13:09 [pubmed]
PHST- 2023/06/06 08:03 [entrez]
AID - L-00293-2022 [pii]
AID - 10.1152/ajplung.00293.2022 [doi]
PST - ppublish
SO  - Am J Physiol Lung Cell Mol Physiol. 2023 Aug 1;325(2):L114-L124. doi: 
      10.1152/ajplung.00293.2022. Epub 2023 Jun 6.