tPA-S⁴⁸¹A Prevents Impairment of Cerebrovascular Autoregulation by Endogenous tPA after Traumatic Brain Injury by Upregulating p38 MAPK and Inhibiting ET-1

Abstract

Traumatic brain injury (TBI) is associated with loss of cerebrovascular autoregulation, which leads to cerebral hypoperfusion. Mitogen activated protein kinase (MAPK) isoforms ERK, p38, and JNK and endothelin-1 (ET-1) are mediators of impaired cerebral hemodynamics after TBI. Excessive tissue plasminogen activator (tPA) released after TBI may cause loss of cerebrovascular autoregulation either by over-activating N-methyl-D-aspartate receptors (NMDA-Rs) or by predisposing to intracranial hemorrhage. Our recent work shows that a catalytically inactive tPA variant (tPA-S 481 A) that competes with endogenous wild type (wt) tPA for binding to NMDA-R through its receptor docking site but that cannot activate it, prevents activation of ERK by wt tPA and impairment of autoregulation when administered 30 min after fluid percussion injury (FPI). We investigated the ability of variants that lack proteolytic activity but bind/block activation of NMDA-Rs by wt tPA (tPA-S

tPA variant tPA‐A296–299 Prevents impairment of cerebral autoregulation and necrosis of hippocampal neurons after stroke by inhibiting upregulation of ET‐1

“…When cAMP is decreased, the net result is elevation of JNK and reduction in p38 (Figure , right pathway). Since p38 is a negative regulator of ET‐1 (Armstead et al, ), ET‐1 levels rise, which impairs autoregulation (Armstead, ; Armstead et al, ). This is consistent with our prior finding that release of endogenous tPA after TBI reverses NMDA‐R‐mediated vasodilation to vasoconstriction, imparing cerebral autoregulation, through a JNK‐dependent intracellular signaling pathway (Armstead et al, ).…”

Microparticles Impair Hypotensive Cerebrovasodilation and Cause Hippocampal Neuronal Cell Injury after Traumatic Brain Injury

“…23,34 ERK-MAPK has been identified as the common downstream mediator of both tPA and ET-1. [28][29][30]34,35 We have recently demonstrated the role of tPA in driving ET-1 release after FPI. 30 In this study, MP elevation leads to elevations in tPA, ET-1, and ERK-MAPK which are prevented with post-injury MP-lysis by PEG-TB administration, suggesting that MP elevations lead to tPA elevations which in turn drive ET-1 release, ERK-MAPK phosphorylation, and disordered Kchannel dilation in response to hypotension and prostaglandins.…”

“…[28][29][30]34,35 We have recently demonstrated the role of tPA in driving ET-1 release after FPI. 30 In this study, MP elevation leads to elevations in tPA, ET-1, and ERK-MAPK which are prevented with post-injury MP-lysis by PEG-TB administration, suggesting that MP elevations lead to tPA elevations which in turn drive ET-1 release, ERK-MAPK phosphorylation, and disordered Kchannel dilation in response to hypotension and prostaglandins. Hypotension after TBI is associated with poor outcome in observational trials of adult and pediatric patients, 4-7 so we believe the role of MPs after TBI is clinically relevant.…”

“…27 Several key mediators in the pathway of this dysfunctional cerebrovascular autoregulation after TBI have been identified, including tissue plasminogen activator (tPA), endothelin-1 (ET-1), and activation of the extracellular signal-regulated kinases (ERK) isoform of a family of mitogen-activated protein kinases (ERK-MAPK). 23,[28][29][30][31] We therefore hypothesized that MPs released after TBI impair hypotensive cerebrovasodilation, PEG-TB protects this vascular response via MP lysis, and investigated the relationship between MPs, tPA, ET-1, and ERK-MAPK in that process.…”

Vascular and non‐vascular contributors to memory reduction during traumatic brain injury

“…Thus, it is possible that memory impairment during TBI could be in part due to reduced cerebrovascular autoregulation. Impaired cerebrovascular autoregulation is associated with increased production of the vasoconstrictor endothelin‐1 (ET‐1) (Armstead et al., ). In addition, ET‐1 antagonizes N‐methyl‐D‐aspartate (NMDA) receptor‐mediated vasodilation (Armstead, ) leading to cerebral hypoperfusion.…”