Directed glia‐assisted angiogenesis in a mature neurosensory structure: Pericytes mediate an adaptive response in human dental pulp that maintains blood‐barrier function

Abstract

The specialized tightly controlled microcirculation of craniofacial neurosensory organs is an essential evolutionary adaptation and yet a dilemma where angiogenic remodeling occurs. Despite extreme plasticity of neurosensory structures, the capacity to reconcile barrier phenotype of the microcirculation with an angiogenic cascade is not known. Here we provide primary evidence for such a response in an elemental neurosensory structure, human dental pulp, following chronic carious insult. In response to hypoxic challenge neurosensory odontoblasts express hypoxia-inducible factor-1α and notch-1. Associated radial rearrangement of astrocyte-like telacytes that communicate through a cell-poor zone with the microvasculature is observed. Activated pericytes characterized by expression of α-smooth muscle actin are located adjacent to the telacyte attachment to the vasculature. In this location, endothelial expression of sonic hedgehog parallels expression of notch-1 by pericytes. The angiogenic response is initiated by pericyte contraction and altered endothelial polarity and proliferation leading to intussusception of endothelial cells and extensive remodeling of basement membrane with upregulation of laminin-8 and laminin-5. These responses guide intravascular loop formation that maintains both intact basement membrane and tight junctions. This initial phase is followed by formation of anastomoses that enhance the hemodynamic capacity of the intravascular loops. The formation of anastomoses is mediated by extension of cytonemes from pericytes guided by MHC-II(+)/CD-163(+) microglia aligned with the telacytes. The cytonemes seek out pericytes on adjacent intravascular loops to initiate migration of endothelial cells. These findings support a new paradigm for understanding angiogenic capacity of neurosensory structures and aberrations of this response manifest as neurovasculopathies.

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

“…Hypoxia-inducible factors (HIFs), composed of oxygen-regulated α subunits and a stable β subunit (3), are essential for mediating adaptive responses to hypoxia and tissue ischemia (4,5). The mammalian genome encodes 3 HIFα isoforms that can form heterodimers with β subunit and drive gene transcription by recognizing and binding hypoxia response elements (HREs) in gene promoters (6,7).…”

Neural microvascular pericytes contribute to human adult neurogenesis

“…Pulp tissue was retrieved as described previously (Farahani et al, ; Farahani et al, ) and fixed in 2% paraformaldehyde/5% sucrose in 0.02 M phosphate buffer pH:7.4 (680 mOsm) for 4 hr at 4 °C. The fixed samples were demineralized in 10% Ethylenediaminetetraacetic acid (EDTA) dissolved in 0.1 M Tris buffer (pH 6.95) for 7 days at 4 °C.…”

“…Human peripheral dental pulp (PDP) accommodates the most elemental blueprint of a peripheral neurosensory structure. In a clearly demarcated trilaminar architecture reminiscent of the SVZ (Farahani, Sarrafpour, Simonian, Li, & Hunter, ; Farahani, Simonian, & Hunter, ), odontoblasts (sensory cells) communicate with a supporting glio‐vascular assembly through an intermediate cell‐free zone. Notably, the glio‐vascular assembly is bistable and local stressors, such as carious insult, trigger angiogenic remodeling of the terminal microvasculature (Farahani et al, ).…”

“…In a clearly demarcated trilaminar architecture reminiscent of the SVZ (Farahani, Sarrafpour, Simonian, Li, & Hunter, ; Farahani, Simonian, & Hunter, ), odontoblasts (sensory cells) communicate with a supporting glio‐vascular assembly through an intermediate cell‐free zone. Notably, the glio‐vascular assembly is bistable and local stressors, such as carious insult, trigger angiogenic remodeling of the terminal microvasculature (Farahani et al, ). A similar angiogenic remodeling was documented in a seminal study by Palmer et al (Palmer, Willhoite, & Gage, ) of adult hippocampal neurogenesis.…”

Putting the Mouth into Health: The Importance of Oral Health for General Health

“…This response provides vascular remodelling whilst maintaining a blood barrier. The directional expansion of the microvasculature is achieved through glial-assisted guided migration of endothelial cells [ 22 ]. This important function can be compared with other glial cell activities in the nervous system.…”