Inhibition of integrin α<sub>V</sub>β<sub>3</sub>prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia

Kiessling, J. Willis; Cines, Douglas B.; Higazi, Abd Al‐Roof; Armstead, William M.

doi:10.1152/ajpheart.01141.2008

Cited by 6 publications

(4 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously shown that uPA binds directly to ␣ V ␤ 3 (17,24) and that plasminogen activators can promote the formation of a signal-transducing complex between low-density lipoprotein receptor and ␣ V ␤ 3 (1). The results of a more recent study extend these initial observations and indicate that uPA released after cerebral H/I impairs pial artery dilation induced by hypercapnia and hypotension through an integrin ␣ V ␤ 3 -dependent process (14). However, other as yet undefined mechanisms, which may include the opioid nociceptin/orphanin FQ and/or the activation of the N-methyl-D-aspartate receptor (2), may also contribute to the cerebrovascular derangement following cerebral H/I.…”

Section: Discussionsupporting

confidence: 71%

PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

Armstead

Riley²,

Kiessling³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

Babies are frequently exposed to cerebral hypoxia and ischemia (H/I) during the perinatal period as a result of stroke, problems with delivery, or postdelivery respiratory management. The sole approved treatment for acute stroke is tissue type plasminogen activator. H/I impairs pial artery dilation (PAD) induced by hypercapnia and hypotension, the impairment aggravated by type plasminogen activator and attenuated by the plasminogen activator inhibitor-1-derived peptide EEIIMD. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is upregulated after H/I and ERK contribute to impaired cerebrovasodilation. This study determined the roles of p38 and JNK MAPK in the impairment of dilation post-H/I in pigs equipped with a closed cranial window and the relationship between alterations in MAPK isoforms and EEIIMD-mediated cerebrovascular protection. Cerebrospinal fluid-phosphorylated (activated) p38 MAPK, but not JNK MAPK, was increased after H/I, an effect potentiated by intravenous EEIIMD administered 1 h postinjury. PAD in response to hypercapnia and hypotension was blunted by H/I, but dilation was maintained by EEIIMD. PAD was further impaired by the p38 antagonist SB-203580 but unchanged by the JNK antagonist SP-600125. Isoproterenol-induced PAD was unchanged by H/I, EEIIMD, SB-203580, and SP-600125. These data indicate that postinjury treatment with EEIIMD attenuated impaired cerebrovasodilation post-H/I by upregulating p38 but not JNK. These data suggest that plasminogen activator inhibitor-1-based peptides and other approaches to upregulate p38 may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy for diverse central nervous system disorders associated with H/I.

show abstract

Section: Discussionsupporting

confidence: 71%

PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

Armstead

Riley²,

Kiessling³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moving to large animal studies, Kiessling et al ( 33 ) described that inhibition of uPA could prevent vasodilatation, suggesting new therapeutic possibilities for clinical practice. On top of that, three other studies ( 36 , 37 , 39 ) described the effects of nociceptin/orphanin FQ and of Protein Tyrosine Kinase, showing that both can partially prevent hypotensive pial dilation impairment, when coadministred with the NMDA antagonist MK801.…”

Section: Resultsmentioning

confidence: 99%

Pathophysiology of Cerebral Hyperperfusion in Term Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review for Future Research

et al. 2021

View full text Add to dashboard Cite

Worldwide neonatal hypoxic-ischemic encephalopathy (HIE) is a common cause of mortality and neurologic disability, despite the implementation of therapeutic hypothermia treatment. Advances toward new neuroprotective interventions have been limited by incomplete knowledge about secondary injurious processes such as cerebral hyperperfusion commonly observed during the first 1–5 days after asphyxia. Cerebral hyperperfusion is correlated with adverse neurodevelopmental outcome and it is a process that remains poorly understood. In order to provide an overview of the existing knowledge on the pathophysiology and highlight the gaps in current understanding of cerebral hyperperfusion in term animals and neonates with HIE, we performed a systematic research. We included papers scoping for study design, population, number of participants, study technique and relevant findings. Methodological quality was assessed using the checklist for cohort studies from The Joanna Briggs Institute. Out of 2,690 results, 34 studies were included in the final review—all prospective cohort studies. There were 14 studies of high, 17 moderate and 3 of low methodological quality. Data from the literature were analyzed in two main subjects: (1) Hemodynamic Changes subdivided into macro- and microscopic hemodynamic changes, and (2) Endogenous Pathways which was subdivided into N-methyl-D-aspartate/Mitogen activated protein kinase (NDMA/MAPK), Nitric Oxide (NO), prostanoids and other endogenous studies. Cerebral hyperperfusion in term neonates with HIE was found to be present 10–30 min after the hypoxic-ischemic event and was still present around day 10 and up to 1 month after birth. Cerebral hyperperfusion was also characterized by angiogenesis and cerebral vasodilation. Additionally, cerebral vasodilation was mediated by endogenous pathways such as MAPK through urokinase Plasminogen Activator (uPA), by neuronal NO synthase following NMDA and by prostanoid synthesis. Future research should elucidate the precise role of NMDA, MAPK and prostanoids in cerebral hyperperfusion. Moreover, research should focus on possible interventions and the effect of hypothermia on hyperperfusion. These findings should be taken into account simultaneously with brain imagining techniques, becoming a valuable asset in assessing the impact in neurodevelopmental outcome.

show abstract

“…tPA and uPA signaling mediation by integrin α v β 3 may also influence cerebrovascular tone through inhibition of important vasodilator stimuli such as autoregulation during hypotension and hypercapnia following global cerebral hypoxia/ischemia (Armstead et al. 2005b; Kiessling et al. 2009a).…”

Section: Tpa‐mediated Signaling Cerebral Hemodynamics and Outcome Amentioning

confidence: 99%

“…The effect of tPA on vascular tone may result from direct interaction with vascular smooth muscle cells to which it signals via the integrin a v b 3 to elicit vasoconstriction in a non-proteolytic manner . tPA and uPA signaling mediation by integrin a v b 3 may also influence cerebrovascular tone through inhibition of important vasodilator stimuli such as autoregulation during hypotension and hypercapnia following global cerebral hypoxia/ischemia (Armstead et al 2005b;Kiessling et al 2009a). Signaling is terminated through binding of PAI-1 by tPA, internalization of the integrin-tPA-PAI-1 ternary complex via LRPmediated endocytosis and dissociation of tPA-PAI-1 from the integrin .…”

Section: Tpa-mediated Signaling Cerebral Hemodynamics and Outcome Amentioning

confidence: 99%

Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders

Armstead

Ganguly

Kiessling

et al. 2010

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Abbreviations used: BBB, blood-brain barrier; ERK, extracellular signal related kinase; ET, endothelin; FPI, fluid percussion brain injury; ICH, intracerebral hemorrhage; JNK, c-Jun-N-terminal kinase; LRP, low-density receptor-related protein; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NVU, neurovascular unit; PA, plasminogen activator; PAI-1, PA inhibitor I; RBC, red blood cells; TBI, traumatic brain injury; tPA, tissue-type plasminogen activator; uPA, urokinase plasminogen activator. AbstractStroke is a leading cause of morbidity and mortality. While tissue-type plasminogen activator (tPA) remains the only FDA-approved treatment for ischemic stroke, clinical use of tPA has been constrained to roughly 3% of eligible patients because of the danger of intracranial hemorrhage and a narrow 3 h time window for safe administration. Basic science studies indicate that tPA enhances excitotoxic neuronal cell death. In this review, the beneficial and deleterious effects of tPA in ischemic brain are discussed along with emphasis on development of new approaches toward treatment of patients with acute ischemic stroke. In particular, roles of tPA-induced signaling and a novel delivery system for tPA administration based on tPA coupling to carrier red blood cells will be considered as therapeutic modalities for increasing tPA benefit/ risk ratio. The concept of the neurovascular unit will be discussed in the context of dynamic relationships between tPA-induced changes in cerebral hemodynamics and histopathologic outcome of CNS ischemia. Additionally, the role of age will be considered since thrombolytic therapy is being increasingly used in the pediatric population, but there are few basic science studies of CNS injury in pediatric animals. Keywords: cerebral ischemia, neurovascular unit, pediatric, signaling, stroke, tissue plasminogen activator. BackgroundThe Word Health Organization defines stroke as 'rapidly developing signs of focal or global disturbance of cerebral function, with symptoms lasting 24 h or longer leading to death, with no apparent cause other than that of vascular origin'. Stroke is the third leading cause of morbidity and mortality after heart disease and cancer. Surviving stroke victims often face serious long-term disability and constitute a significant familial and societal economic burden. Stroke can be classified broadly into ischemic or hemorrhagic, with the former comprising 80% of cases. Ischemic stroke, in turn, can be further subclassified as thrombotic or embolic in origin. Thrombotic stroke occurs when a clot forms in an artery located within the brain whereas an embolic stroke results from a clot formed elsewhere in the body that is subsequently transported to the brain. Hemorrhagic stroke results from the disruption of vascular integrity or aneurysm sufficient to cause bleeding within the brain. Generally speaking, three major approaches have been used in the treatment of acute stroke: neuroprotection, thrombolysis, and clot removal. To date, neuroprotection ha...

show abstract

Inhibition of integrin α_Vβ₃prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia

Abstract: Kiessling JW, Cines DB, Higazi AA, Armstead WM. Inhibition of integrin ␣V␤3 prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia.

Cited by 6 publications

References 38 publications

PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

Pathophysiology of Cerebral Hyperperfusion in Term Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review for Future Research

Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders

Contact Info

Product

Resources

About

Inhibition of integrin αVβ3prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia

Abstract: Kiessling JW, Cines DB, Higazi AA, Armstead WM. Inhibition of integrin ␣V␤3 prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia.

Cited by 6 publications

References 38 publications

PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

PAI-1-derived peptide EEIIMD prevents impairment of cerebrovasodilation by augmenting p38 MAPK upregulation after cerebral hypoxia/ischemia

Pathophysiology of Cerebral Hyperperfusion in Term Neonates With Hypoxic-Ischemic Encephalopathy: A Systematic Review for Future Research

Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders

Contact Info

Product

Resources

About

Inhibition of integrin α_Vβ₃prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia