Perlecan regulates pericyte dynamics in the maintenance and repair of the blood–brain barrier

Abstract

Ischemic stroke causes blood–brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan (Hspg2)-deficient (Hspg2−/−-TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2−/−-TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB–induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke.

Review of Alterations in Perlecan-Associated Vascular Risk Factors in Dementia

“…Perlecan was found to be lower in non-human primate models of focal cerebral ischemia [63,169], whereas DV has been demonstrated to increase in rodent models of stroke (endothelin-1 and tandem common carotid artery occlusion and distal middle cerebral artery occlusion) [18]. The therapeutic potential of recombinant DV after ischemic stroke has been demonstrated by us and others [18,40]. Correspondingly, the lack of perlecan, when using hypomorphs, Col2a1-Hspg2 TG/− and Hspg2 −/− mice, was associated with larger infarcts as well as worse functional outcomes after MCAo and decreased neurogenesis, respectively [18,40].…”

“…The therapeutic potential of recombinant DV after ischemic stroke has been demonstrated by us and others [18,40]. Correspondingly, the lack of perlecan, when using hypomorphs, Col2a1-Hspg2 TG/− and Hspg2 −/− mice, was associated with larger infarcts as well as worse functional outcomes after MCAo and decreased neurogenesis, respectively [18,40]. Increased perlecan expression was found following traumatic brain injury in mice [75] as well as in human samples from patients with brain arteriovenous malformation [170].…”

“…Truncated perlecan DI, found in Hspg2 −/− or perlecan knock out mice, has been associated with complete loss of function, embryonic lethality (~E10-12), enlarged ventricles, smaller brains, and weakened vasculature leading to severe bleeding and heart malformations [24,25,37]. Rescuing this phenotype via cartilage-specific perlecan (Hspg2 −/− ; Col2a1-Hspg2 TG/− ) knock in [38] results in 50% more survivability at~E10-12 [39], normal cephalic development [39], intact BBB [40], but decreased neurogenesis [41], and endothelial [42] and pericyte [40] dysfunction following injury. Interestingly, an altered attachment site of DI for HS side chains, due to the lack of exon 3 (Hspg2 ∆3/∆3 ), did not affect perlecan expression [43], nor associated with birth defects or phenotypic developmental abnormalities other than congenital cataracts [43].…”

“…As these vessels dive into the brain parenchyma and branch into smaller and smaller segments, they give rise to brain arteriole and capillary networks, while losing their smooth muscle (SMC) coverage but gaining more pericytes and astrocytic endfeet. All of these cells regulate and/or secrete perlecan [15,40,[69][70][71][72][73][74][75][76]. Studies investigating the effects of altered perlecan expression are contradictory, ranging from pro vs. anti-angiogenic [17,18,70,77], or associated or not with plaque and thrombotic core proteins [78][79][80][81][82][83][84].…”

Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

“…Integrin α5β1 mediates leukocyte infiltration and subsequent BBB dysfunction; the integrin α5β1 inhibitor, ATN-161, can preserve claudin-5 and collagen-IV expression and reduce MMP-9 transcription, thus protecting BBB integrity (Edwards et al, 2019). Perlecan, a major heparan sulfate proteoglycan component of the BM, can maintain and repair the injured BBB by reinforcing the BM (Nakamura et al, 2019). Furthermore, release of microvesicles by ECs can upregulate ZO-1 and claudin-5 expression, thereby ameliorating BBB disruption and reducing infarct volume (Pan et al, 2016).…”