Physiological cerebrovascular remodeling in response to chronic mild hypoxia: A role for activated protein C

Abstract

Activated protein C (APC) is a serine protease that promotes favorable changes in vascular barrier integrity and post-ischemic angiogenic remodeling in animal models of ischemic stroke, and its efficacy is currently being investigated in clinical ischemic stroke trials. Interestingly, application of sub-clinical chronic mild hypoxia (CMH) (8% O2) also promotes angiogenic remodeling and increased tight junction protein expression, suggestive of enhanced blood-brain barrier (BBB) integrity, though the role of APC in mediating the influence of CMH has not been investigated. To examine this potential link, we studied CMH-induced cerebrovascular remodeling after treating mice with two different reagents: (i) a function-blocking antibody that neutralizes APC activity, and (ii) exogenous recombinant murine APC. While CMH promoted endothelial proliferation, increased vascular density, and upregulated the angiogenic endothelial integrins α5β1 and αvβ3, these events were almost completely abolished by functional blockade of APC. Consistent with these findings, addition of exogenous recombinant APC enhanced CMH-induced endothelial proliferation, expansion of total vascular area and further enhanced the CMH-induced right-shift in vessel size distribution. Taken together, our findings support a key role for APC in mediating physiological remodeling of cerebral blood vessels in response to CMH.

Activated Protein C Attenuates Experimental Autoimmune Encephalomyelitis Progression by Enhancing Vascular Integrity and Suppressing Microglial Activation

“…and that this is associated with upregulated expression of fibronectin and its receptor α5β1 integrin on spinal cord blood vessels (Boroujerdi et al, 2013). In a different model, we showed that chronic mild hypoxia stimulates angiogenic remodeling and interestingly found that APC appears to plays a key role in mediating this response, as functional blockade of APC prevented both upregulation of the fibronectin-α5β1 integrin axis and the associated angiogenic response, while in contrast, exogenous APC enhanced this response (Burnier et al, 2016). In light of these findings, we wondered if the protective effect of APC in EAE might be due to enhanced fibronectin-α5β1 integrin signaling driving a stronger angiogenic response.…”

“…Based on our previous findings that during the presymptomatic phase of EAE, a marked vascular remodeling response occurs (Boroujerdi et al, 2013), and that APC plays a key role in mediating cerebrovascular remodeling in response to chronic mild hypoxia (Burnier et al, 2016), we wondered if the protective effect of APC in EAE might, in part, be the result of upregulated fibronectin-α5β1 integrin signaling driving an enhanced angiogenic response. However surprisingly, APCtreated mice showed no appreciable differences in their vascular expression of fibronectin or α5β1 integrin or their overall level of vascularity, compared to vehicle-treated control mice.…”

“…Based on this incomplete and at times conflicting data, we embarked on the current study with the objective of clarifying whether APC protects against demyelinating disease, as well as seek to define the molecular mechanisms underlying this protection. In particular, in light of the importance of vascular breakdown and remodeling in the pathogenesis of EAE (Gay and Esiri, 1991;Kirk et al, 2003;Roscoe et al, 2009;Seabrook et al, 2010), and our recent finding that APC promotes physiological cerebrovascular remodeling (Burnier et al, 2016), we specifically wanted to examine whether APC protects in EAE via promotion of vascular remodeling. Thus, this study had the following specific goals: (i) evaluate the therapeutic potential of APC in the chronic progressive form of EAE, and (ii) examine how APC influences pathogenic events at the cellular level, paying particular attention to its effects on vascular breakdown and remodeling, leukocyte infiltration, loss of endothelial tight junction proteins, and glial activation.…”

Physiological and Pathological Remodeling of Cerebral Microvessels

“…However, the mechanism might not be so simple since other factors are no less important. For instance, the accumulation of protein C in the brain tissue in the postischemic period stimulates endothelial proliferation, increases vascular density, and activates pro-angiogenic integrins α5β1 and avβ3 [ 27 ]. In parallel, protein C suppresses apoptosis of brain endothelial cells in ischemia [ 28 ], thereby preventing the reduction of the capillary bed.…”

Neuroinflammation is a putative target for the prevention and treatment of perioperative neurocognitive disorders

“…54 APOε4 mice have a permeable BBB which can be reversed by inhibiting the pro-inflammatory cyclophilin A pathway 55 ; however, inhibitors of cyclophilin A have yet to materialize into the clinical arena. Also, activated protein C can also improve endothelial barrier integrity 56 ; again, this information has yet to be translated into clinical utility.…”