PMID- 31261126
OWN - NLM
STAT- MEDLINE
DCOM- 20200824
LR  - 20210110
IS  - 1092-0684 (Electronic)
IS  - 1092-0684 (Linking)
VI  - 47
IP  - 1
DP  - 2019 Jul 1
TI  - Flow-induced, inflammation-mediated arterial wall remodeling in the formation and 
      progression of intracranial aneurysms.
PG  - E21
LID - 2019.5.FOCUS19234 [pii]
LID - 10.3171/2019.5.FOCUS19234 [doi]
AB  - OBJECTIVE: Unruptured intracranial aneurysms (UIAs) are relatively common lesions 
      that may cause devastating intracranial hemorrhage, thus producing considerable 
      suffering and anxiety in those affected by the disease or an increased likelihood 
      of developing it. Advances in the knowledge of the pathobiology behind 
      intracranial aneurysm (IA) formation, progression, and rupture have led to 
      preclinical testing of drug therapies that would prevent IA formation or 
      progression. In parallel, novel biologically based diagnostic tools to estimate 
      rupture risk are approaching clinical use. Arterial wall remodeling, triggered by 
      flow and intramural stresses and mediated by inflammation, is relevant to both. 
      METHODS: This review discusses the basis of flow-driven vessel remodeling and 
      translates that knowledge to the observations made on the mechanisms of IA 
      initiation and progression on studies using animal models of induced IA 
      formation, study of human IA tissue samples, and study of patient-derived 
      computational fluid dynamics models. RESULTS: Blood flow conditions leading to 
      high wall shear stress (WSS) activate proinflammatory signaling in endothelial 
      cells that recruits macrophages to the site exposed to high WSS, especially 
      through macrophage chemoattractant protein 1 (MCP1). This macrophage infiltration 
      leads to protease expression, which disrupts the internal elastic lamina and 
      collagen matrix, leading to focal outward bulging of the wall and IA initiation. 
      For the IA to grow, collagen remodeling and smooth muscle cell (SMC) 
      proliferation are essential, because the fact that collagen does not distend much 
      prevents the passive dilation of a focal weakness to a sizable IA. Chronic 
      macrophage infiltration of the IA wall promotes this SMC-mediated growth and is a 
      potential target for drug therapy. Once the IA wall grows, it is subjected to 
      changes in wall tension and flow conditions as a result of the change in geometry 
      and has to remodel accordingly to avoid rupture. Flow affects this remodeling 
      process. CONCLUSIONS: Flow triggers an inflammatory reaction that predisposes the 
      arterial wall to IA initiation and growth and affects the associated remodeling 
      of the UIA wall. This chronic inflammation is a putative target for drug therapy 
      that would stabilize UIAs or prevent UIA formation. Moreover, once this coupling 
      between IA wall remodeling and flow is understood, data from patient-specific 
      flow models can be gathered as part of the diagnostic workup and utilized to 
      improve risk assessment for UIA initiation, progression, and eventual rupture.
FAU - Frosen, Juhana
AU  - Frosen J
AD  - 1Department of Neurosurgery, and.
AD  - 2Hemorrhagic Brain Pathology Research Group, Kuopio University Hospital, Kuopio, 
      Finland.
FAU - Cebral, Juan
AU  - Cebral J
AD  - 3Bioengineering Department, Volgenau School of Engineering, George Mason 
      University, Fairfax, Virginia.
FAU - Robertson, Anne M
AU  - Robertson AM
AD  - 4Department of Mechanical Engineering and Materials Science, University of 
      Pittsburgh, Pittsburgh, Pennsylvania; and.
FAU - Aoki, Tomohiro
AU  - Aoki T
AD  - 5Department of Molecular Pharmacology, Research Institute, and.
AD  - 6Core Research for Evolutional Science and Technology (CREST) from Japan Agency 
      for Medical Research and Development (AMED), National Cerebral and Cardiovascular 
      Center, Suita, Osaka, Japan.
LA  - eng
GR  - R01 NS097457/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Neurosurg Focus
JT  - Neurosurgical focus
JID - 100896471
SB  - IM
MH  - Cerebral Arteries/*pathology
MH  - *Cerebrovascular Circulation
MH  - Humans
MH  - Hydrodynamics
MH  - Inflammation/complications/*pathology
MH  - Intracranial Aneurysm/etiology/*pathology
MH  - Models, Biological
MH  - Stress, Physiological
PMC - PMC7193287
MID - NIHMS1579748
OTO - NOTNLM
OT  - CFD = computational fluid dynamics
OT  - COX2 = cyclooxygenase 2
OT  - EC = endothelial cell
OT  - IA = intracranial aneurysm
OT  - IEL = internal elastic lamina
OT  - MCP1 = macrophage chemotactic protein 1
OT  - NFkB = nuclear factor kappa b
OT  - NO = nitric oxide
OT  - PDGF-B = platelet-derived growth factor B
OT  - PGE2 = prostaglandin E2
OT  - PPAR = peroxisome proliferator-activated receptor
OT  - SMC = smooth muscle cell
OT  - TGFb = transforming growth factor beta
OT  - UIA = unruptured IA
OT  - VCAM1 = vascular cell adhesion molecule 1
OT  - WSS = wall shear stress
OT  - WSSG = WSS gradient
OT  - WT = wall tension
OT  - aSAH = aneurysmal subarachnoid hemorrhage
OT  - bAVM = brain arteriovenous malformation
OT  - eNOS = endothelial NO synthase
OT  - flow
OT  - inflammation
OT  - intracranial aneurysm
OT  - remodeling
OT  - risk of rupture
EDAT- 2019/07/02 06:00
MHDA- 2020/08/25 06:00
PMCR- 2020/05/01
CRDT- 2019/07/02 06:00
PHST- 2019/03/03 00:00 [received]
PHST- 2019/05/01 00:00 [accepted]
PHST- 2019/07/02 06:00 [entrez]
PHST- 2019/07/02 06:00 [pubmed]
PHST- 2020/08/25 06:00 [medline]
PHST- 2020/05/01 00:00 [pmc-release]
AID - 2019.5.FOCUS19234 [pii]
AID - 10.3171/2019.5.FOCUS19234 [doi]
PST - ppublish
SO  - Neurosurg Focus. 2019 Jul 1;47(1):E21. doi: 10.3171/2019.5.FOCUS19234.