Bioelectric impact of pathological angiogenesis on vascular function

Abstract

Pathological angiogenesis, as seen in many inflammatory, immune, malignant, and ischemic disorders, remains an immense health burden despite new molecular therapies. It is likely that further therapeutic progress requires a better understanding of neovascular pathophysiology. Surprisingly, even though transmembrane voltage is well known to regulate vascular function, no previous bioelectric analysis of pathological angiogenesis has been reported. Using the perforated-patch technique to measure vascular voltages in human retinal neovascular specimens and rodent models of retinal neovascularization, we discovered that pathological neovessels generate extraordinarily high voltage. Electrophysiological experiments demonstrated that voltage from aberrantly located preretinal neovascular complexes is transmitted into the intraretinal vascular network. With extensive neovascularization, this voltage input is substantial and boosts the membrane potential of intraretinal blood vessels to a suprahyperpolarized level. Coincident with this suprahyperpolarization, the vasomotor response to hypoxia is fundamentally altered. Instead of the compensatory dilation observed in the normal retina, arterioles constrict in response to an oxygen deficiency. This anomalous vasoconstriction, which would potentiate hypoxia, raises the possibility that the bioelectric impact of neovascularization on vascular function is a previously unappreciated pathophysiological mechanism to sustain hypoxia-driven angiogenesis.neovascularization | proliferative retinopathy | retinopathy of prematurity | proliferative diabetic retinopathy | retina T he abnormal growth of blood vessels is a key pathophysiological feature of numerous disorders, including tumorigenesis, arthritis, endometriosis, and retinopathies. Despite substantial progress from studies of patients and animal models, abnormal neovascularization remains a common threat to health and wellbeing. To help address this challenge, we devised a unique experimental approach to better understand neovascular pathophysiology. Because almost nothing is known about the electrogenic profile of neovascular complexes and how these complexes functionally interact with their parent vessels, we focused on the bioelectric features of neovascularization. These gaps in knowledge are surprising, considering that it is well established that the transmembrane voltage of vascular cells (1), as well as electrotonic cell-cell interactions within a vascular network (2-4), play vital roles in regulating blood flow.In this electrophysiological analysis of pathological angiogenesis, we focused on abnormal vasoproliferation in rodent and human retinas. For multiple reasons, the retina is an ideal tissue for this undertaking. First is its clinical importance. Retinal vasoproliferation is the major cause of blindness in prematurely born infants (retinopathy of prematurity) and persons with diabetes (proliferative diabetic retinopathy) and sickle cell disease (sickle cell retinopathy). The hallmark of these disorders is abno...

Angiogenic neovessels promote tissue hypoxia

“…In summary, the findings reported by Puro et al (5) raise the intriguing suggestion that pathological angiogenesis attempts to self-promote by maintaining a hypoxic state around it, and suggest many new avenues of research-both in the fields of retinopathy as well as cancer-in understanding and possibly interrupting this process with therapeutic intent.…”

“…1). Although these findings fit together, future research should focus on establishing the causality and temporal sequence of these maladaptive processes to better understand the relationship between hypoxia, neurovascular coupling, capillary death, and neovascularization in retinal diseases; this could be done using in vitro preparations like those used by Puro et al (5) and also corroborated using in vivo retinal preparations (14).…”

“…The suggestion that the reversal of the hypoxia-evoked vasomotor response might contribute to a state of continued hypoxia is an interesting hypothesis advanced by Puro et al (5). On the other hand, the resting suprahyperpolarization is expected to alter the basal tone of these vascular smooth-muscle cells and therefore to increase the luminal diameter of both the neovessels and the retinal vessels proximal to the neovessels.…”

“…Scientists have long sought after antiangiogenic drugs to limit neovascularization to limit the progression of these pathologies (2). In PNAS, Puro et al (5) report an intriguing new finding about the properties of these neovessels using a model of retinal pathological angiogenesis: that these neovessels have a suprahyperpolarized membrane potential, which spreads to neighboring segments of the normal vasculature and reverses their vasomotor response to hypoxic stimuli, causing them to constrict and thus promoting further hypoxia.…”

“…Furthermore, the retina has a very organized vascular anatomy and clinically presents with pronounced neovascularization in several disease states, including retinopathy of prematurity and diabetic retinopathy (4). Puro et al (5) used two different animal models of oxygen-induced retinal neovascularization and characterized the new vessels that subsequently sprouted from existing retinal vessels into the vitreous. The authors find that mural cells on these neovessels are much more hyperpolarized than those on normal vessels in healthy retinas.…”