Remodeling of Cerebral Microcirculation after Ischemia-Reperfusion

Abstract

Clinical and experimental studies have been focused on the pathophysiological mechanisms induced by brain ischemia-reperfusion injury. Recovery events, such as neurogenesis, angiogenesis and the growth of new blood vessels from the preexisting vascular tree, have been intensively studied in the last decades to clarify the vascular remodeling crucial for stroke outcome. This review aims to discuss the cerebral microcirculation remodeling induced by ischemia-reperfusion and the mechanisms involved in angiogenesis and vasculogenesis. The first in vivo observations were focused on anastomotic shunting of cerebral blood flow (CBF) in experimental and clinical models. Thereafter, vascular remodeling induced by cerebral ischemia-reperfusion was reported in mice and rats. Successively, other studies have assessed that within 30 days of middle cerebral artery (MCA) occlusion in rats, there is an increase in CBF and recovery from stroke. Recently, rats submitted to transient MCA occlusion showed pial microcirculation remodeling with the formation of new arterioles sprouting from penumbra vessels and overlapping the ischemic core. This review focuses on the production and/or activation of vasculotrophic factors able to trigger and facilitate microvascular remodeling. Vascular endothelial growth factor and endothelium-released nitric oxide appear to be the main factors involved in the formation of new vessels during microvascular remodeling. These studies are fundamental for consequent interventions on molecular targets, useful for fostering vascular remodeling and the recovery of functions.

Blood−brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury

“…Two key parameters influence restoration of blood flow: presence of collaterals and a capacity to undergo vascular remodeling and produce angiogenic mediators. A majority of the research reveals that spontaneous vascular remodeling occurs after TBI and stroke [71,72 ▪ ,73] with exceptions that show the absence of vascular remodeling depending upon the region of assessment [74], impaired plasticity and remodeling associated with age [75–77] and comorbid conditions [78,79]. Vascular modeling is associated with improved neurological outcomes [73].…”

“…Both stroke and TBI involve BBB disruption, hypoxic states, redox systemimbalance thatleads tothe generation of free radicals, and release of proinflammatory mediators [87]. Each of these events is an essential predecessor to a tissue repair response and is important to evoke a proangiogenic state in the region of injury that creates a feasible canvas for the growth of new vessels [72 ▪ ,87,88]. …”

“…EPCs have been reported to be involved in the migration of neuronal progenitors that localize around the peri-infarct region after stroke [121,123]. Mobilization of EPCs from the bone marrow and peripheral blood has been reported in models of both ischemic stroke and TBI at the site of injury [72 ▪ ]. EPCs are detected as early as 24 h and peak at 48 h after TBI both in the peripheral circulation and around the damaged brain tissue.…”

High incidence of adverse cerebral blood flow responses to spreading depolarization in the aged ischemic rat brain

“…Perfusion deficit during ischemia deepens progressively in the aged but not in the young brain CBF sharply drops after ischemia onset, but compensation through collaterals or vascular remodeling may contribute to slow partial recovery of perfusion (Clark et al, 2014;Lapi and Colantuoni, 2015). Our data indicate that in the ischemia model used, perfusion stabilized and persisted at around 40% till the end of the ischemic period in young rats, but dropped below 20% in old rats, which falls below the CBF threshold of electrical failure of the nervous tissue (Astrup et al, 1977).…”

The impact of aging on spreading depolarization in the intact and ischemic rat brain

“…CBF sharply drops after ischemia onset, but compensation through collaterals or vascular remodeling may contribute to slow partial recovery of perfusion 46,72 . Our data indicate that in the ischemia model used, perfusion stabilized and persisted at around 40% till the end of the ischemic period in young rats, but dropped below 20% in old rats, which falls below the CBF threshold of electrical failure of the nervous tissue 3 .…”