GLI1, short for glioma-associated oncogene family zinc finger 1, is best known as a transcription factor, a protein that switches other genes on or off. It serves as one of the main downstream effectors of the Hedgehog signaling pathway, an ancient communication system that orchestrates embryonic development and, in adults, helps maintain and repair tissues. When Hedgehog signaling is activated, GLI1 is expressed, and its presence in a cell is therefore a readout of that pathway’s activity. What has fascinated vascular biologists over the past ten years is that in adult tissues, GLI1 expression consistently marks a population of perivascular cells, the mesenchymal cells that wrap around and support blood vessels, and that these GLI1-positive cells display striking progenitor-like and injury-responsive properties.

The authors of the review, led by Weiwei Yang, Qingqing Li, Saverio Bellusci, and Xuran Chu, working across institutions in Germany and China, synthesize findings from lineage-tracing and single-cell studies in mice. Lineage tracing is a technique that permanently labels a cell and all of its descendants, allowing researchers to follow where a GLI1-positive cell goes and what it becomes over time. Single-cell technologies, meanwhile, reveal the molecular identities of individual cells within a tissue. Together, these approaches have shown that GLI1-positive perivascular cells are not a static population. They can support vessel stability and contribute to repair after injury, but under pathological conditions they can also be recruited into maladaptive remodeling programs that drive fibrosis, abnormal muscularization of small vessels, and tumor-supportive vasculature.

This duality is the central theme of the review. The key question, the authors argue, is not simply whether GLI1-positive cells are present in a tissue, but which state they have adopted and what signals push them toward one fate or another. A GLI1-positive perivascular cell that differentiates into a smooth muscle-like mural cell and stabilizes a newly formed vessel is performing a regenerative service. The same cell type, responding to chronic inflammatory or hypoxic signals, may instead proliferate excessively, deposit extracellular matrix, and contribute to the stiffened, narrowed vessels characteristic of fibrotic disease. Distinguishing these states, and identifying the molecular switches that control them, is where the therapeutic opportunity lies.

At the molecular level, the review describes how GLI1 pathway activity intersects with several major signaling networks that govern vascular behavior. The vascular endothelial growth factor, or VEGF, pathway drives endothelial cell sprouting during angiogenesis, and Hedgehog signaling has been shown to modulate the availability and effects of VEGF in several contexts. Platelet-derived growth factor signaling recruits mural cells to nascent vessels, a process in which GLI1-positive perivascular cells participate. Transforming growth factor beta signaling, a potent driver of myofibroblast differentiation and matrix deposition, represents the fibrotic arm of the same cellular program. Hypoxia-inducible factor 1 alpha, the master sensor of low oxygen, links tissue hypoxia to both angiogenic activation and, in some settings, Hedgehog pathway upregulation. The interplay among these pathways determines whether a GLI1-positive cell becomes a stabilizing mural cell, a matrix-producing fibroblast-like cell, or a contributor to pathological neovascularization.

The disease settings examined in the review span three major areas. The first is tumor angiogenesis. Solid tumors require new blood vessels to grow beyond a few millimeters in diameter, and the tumor microenvironment co-opts normal vascular biology to build them. Evidence summarized in the review indicates that Hedgehog pathway activity and GLI1-positive perivascular cells contribute to the formation of tumor vasculature in several cancer types, including glioblastoma, where glioblastoma stem cells can themselves engage Hedgehog signaling, as well as non-small cell lung cancer, triple-negative breast cancer, oral squamous cell carcinoma, and salivary adenoid cystic carcinoma. In these contexts, GLI1-positive cells may support vessel formation, stabilize tumor vessels, or contribute to the abnormal vessel architecture that impedes drug delivery while facilitating metastasis.

The second major setting is pulmonary vascular remodeling, a hallmark of pulmonary arterial hypertension and other severe lung diseases, including acute respiratory distress syndrome. In pulmonary arterial hypertension, the small pulmonary arteries undergo dramatic remodeling: smooth muscle cells proliferate, cells that should remain outside the muscle layer acquire muscle-like characteristics in a process called neomuscularization, and the vessel lumen narrows, raising pressure and eventually causing right heart failure. The review discusses evidence that GLI1-positive perivascular cells in the lung can act as progenitors for some of these aberrant smooth muscle-like cells, and that Hedgehog signaling contributes to this maladaptive program. In the injured lung, the same cells may participate in repair after acute injury, highlighting again the state-dependent nature of their behavior.

The third setting is fibrotic vasculopathy, the vascular changes that accompany organ fibrosis in tissues such as liver, kidney, skin, and lung. In the liver, hepatic stellate cells, which are perivascular mesenchymal cells by another name, drive fibrosis in chronic liver disease, and Hedgehog signaling has been implicated in their activation. The review also touches on related populations in other organs, including periodontal ligament stem cells in dental tissues and mesenchymal stem cell niches generally, where GLI1 marks cells with regenerative capacity. Across these systems, the common thread is that perivascular GLI1-positive cells sit at a decision point between repair and scarring, and the extracellular matrix, immune cells, and endothelial cells surrounding them provide the contextual signals that tip the balance.

Importantly, the authors are careful about the strength of the evidence. They explicitly distinguish between settings where direct lineage-based evidence exists, meaning that GLI1-positive cells have been formally shown to give rise to a particular cell type in vivo, and settings where the involvement of these cells is inferential, based on pathway activity or correlative data. This candor matters, because the field of perivascular cell biology has historically suffered from overlapping nomenclature and inconsistent markers. Pericytes, adventitial fibroblasts, mesenchymal stem cells, and smooth muscle cell progenitors are all perivascular mesenchymal populations with partially overlapping features, and GLI1 provides one marker among several. The review also highlights emerging tools, including spatial transcriptomics, which maps gene expression within intact tissue architecture, as a means of resolving where GLI1-positive cells reside and what states they occupy in human disease samples.

On the therapeutic front, the review identifies cell-state-specific nodes as the most realistic targets. Broad inhibition of the Hedgehog pathway with smoothened inhibitors, drugs already approved for certain cancers, has shown clinical limitations and context-dependent effects, because the pathway serves beneficial functions in tissue maintenance and repair. The more nuanced strategy proposed is to target the specific downstream programs that drive maladaptive behavior, such as the interaction between Hedgehog signaling and transforming growth factor beta-driven fibrosis, or the recruitment of GLI1-positive cells into tumor vasculature, while sparing their regenerative roles. The authors also note connections to other pathways, including YAP-dependent mechanotransduction, endothelin-1 signaling, and inflammatory nuclear factor kappa B activation, any of which could provide state-specific leverage points. As an open-access review, the article offers researchers a consolidated map of a rapidly evolving field, and it makes a compelling case that the fate of a single perivascular cell population, watched through the lens of GLI1, may determine whether an injured tissue heals or hardens, whether a tumor is fed or starved, and whether a hypertensive lung remodels relentlessly or can be coaxed back toward stability.

Subject of Research: The role of GLI1-positive perivascular cells in angiogenesis and vascular remodeling

Article Title: GLI1⁺ perivascular cells in angiogenesis and vascular remodeling: mechanisms and disease relevance

Article References: Yang, W., Li, Q., Liu, X., Yang, W., Noori, A., Sotoodeh, L., Chen, M., Xiong, X., Bellusci, S., & Chu, X. (2026). GLI1⁺ perivascular cells in angiogenesis and vascular remodeling: mechanisms and disease relevance. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06412-w

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06412-w

Keywords: GLI1, Hedgehog signaling, perivascular cells, angiogenesis, vascular remodeling, tumor angiogenesis, pulmonary arterial hypertension, fibrosis, lineage tracing, pericytes, VEGF, TGF-beta

The heart is an organ with an unforgiving relationship to its blood supply. Cardiac muscle works continuously and demands a constant delivery of oxygen, which means the coronary vasculature must grow in careful proportion to the muscle it serves. Too little vessel growth starves the tissue; too much creates a disorganized, inefficient network. During development, and again after injury, the heart must therefore solve a problem that engineers would recognize immediately: building the right amount of blood vessel, and knowing precisely when to stop. The new study suggests that the zebrafish heart solves this problem with a dedicated cellular control system, one that had gone unnoticed until now because it only becomes prominent under specific conditions of growth and repair.

The research is rooted in a question that has animated the field for years. Zebrafish possess a remarkable ability that mammals largely lack: after significant injury to the heart, they can regenerate the damaged muscle almost completely, restoring function rather than forming a permanent scar. Understanding how they accomplish this has become a major strategy for identifying the regenerative programs that might, in principle, be reawakened in human patients. Dr. Jingli Cao, associate professor of cell and developmental biology at Weill Cornell Medicine and a member of its Cardiovascular Research Institute, has spent much of his career tracing this process. As a postdoctoral fellow at Duke University, he determined that the epicardium, the thin layer of cells that envelops the heart, provides both the signals and the cells needed to regenerate heart tissue in zebrafish.

The epicardium has long been viewed as more than passive packaging. In response to injury, it activates a specific population of progenitor cells that give rise to the various cell types involved in regenerating heart muscle and coronary blood vessels. But a deeper puzzle remained: what directs these precursor cells to specialize into one fate or another? To answer it, Dr. Cao’s team, including graduate student Björn Perder and postdoctoral fellow Dr. Yu Xia, catalogued the genes that switch on in these cells when the heart is injured. Among the activated genes they identified a master regulator called scxa, a transcription factor that steers a subset of epicardial progenitor cells toward a fate that had never been characterized before.

That fate turned out to be a novel perivascular cell type. Once specified by scxa, these cells migrate to the coronary vessels and surround them, taking up a position that immediately suggested a regulatory role. Perivascular cells in general are known to modulate vessel stability, maturation, and remodeling, so the location of the new cell type was a strong clue. The team found that these cells express a particular type of collagen, and that this collagen does more than provide structural support. The cells process the collagen molecule to release a small protein fragment, a derived signal that ultimately curbs further vessel expansion. In other words, the very cells that accompany the growing vasculature carry within them the molecular message that tells the network when enough is enough.

Dr. Cao framed the significance of this arrangement in practical terms. During development, or when the heart is damaged, the organism needs to build the right amount of blood vessel, and it needs to know when to stop, he noted. The newly discovered system provides that layer of control. This kind of negative feedback is a recurring theme in biology, but identifying the specific cell type and the specific signaling molecule responsible in the heart gives researchers a concrete handle on a process that has been difficult to study. It also suggests that disorders of vascular growth in the heart, whether insufficient vessel formation after injury or excessive, disorganized growth, might be traceable to failures of this regulatory circuit.

Perhaps the most intriguing aspect of the study is what it reveals about timing. The researchers had previously shown that when regions of the heart experience low oxygen levels, a condition known as hypoxia, signals from the epicardium coordinate the growth of heart muscle and coronary vessels so that the two develop in step with each other. The new findings illuminate a plausible mechanism for how this coordination happens. Low oxygen appears to act as an environmental cue that temporarily activates scxa, which in turn directs a subset of epicardial progenitors toward the perivascular fate. These cells then surround the coronary vessels and may help regulate their development and remodeling. Hypoxia, in this model, is not merely a stress signal but an instruction: it tells the epicardium that the tissue is outpacing its blood supply and that vascular support cells are needed now.

This oxygen-sensing logic has an elegant developmental rationale. As heart muscle proliferates, the growing tissue inevitably pushes local oxygen levels down, because diffusion cannot keep pace with expansion. By using hypoxia as the trigger for scxa activation, the heart ensures that vessel-supporting cells are generated exactly where and when the muscle is growing fastest. The same mechanism likely operates after injury, when the damaged tissue becomes hypoxic and the epicardium mounts its regenerative response. If the system works as the study suggests, the perivascular cells and their collagen-derived braking signal would form a self-correcting loop: hypoxia recruits the cells, the cells support vessel growth, and the vessels restore oxygen delivery, at which point the signal to expand fades.

The translational implications are considerable, though the researchers are careful about the distance between zebrafish and humans. Humans do carry a related gene, SCX, but no one yet knows whether human epicardial cells use it in the same way as their zebrafish counterparts. There is a cautionary wrinkle: after an injury such as a heart attack in mammals, SCX is switched on in cardiac fibroblasts, the cells that promote scar tissue formation. In mammals, then, the same regulatory gene appears to be associated with fibrosis rather than regeneration. Dr. Cao suggests that in the future it may be possible to use SCX to reactivate human epicardial cells and steer them toward generating the cells and signals that promote heart regeneration, redirecting the gene’s activity away from scarring and toward repair.

Toward that end, Dr. Cao’s laboratory is working with cultured human epicardial cells and cardiac organoids, laboratory-grown miniature tissue models, to develop ways of using activated cells to repair damaged regions of the heart. The vision is a kind of biological bandage: a living material that could be applied to an injured site and induce controlled growth of both heart muscle and vessels, rebuilding the tissue in a coordinated fashion rather than leaving a non-contractile scar. Dr. Cao is quick to temper expectations, noting that he does not believe a single magic factor controls regeneration. But, as he put it, the team has discovered one more factor, one more mechanism that could eventually contribute to turning on epicardial cells and repairing human hearts. The work was supported by the New York State Stem Cell Science program, the Louis and Rachel Rudin Foundation, the Belgian American Educational Foundation, the American Heart Association, and the National Institutes of Health, reflecting the broad institutional bet that the zebrafish heart still has many secrets worth stealing.

Subject of Research: Discovery of a novel scxa-specified perivascular cell type that regulates coronary vascular development in the regenerating zebrafish heart

Article Title: Newly discovered cell helps shape blood vessel growth in the heart

Article References: Newly discovered cell helps shape blood vessel growth in the heart. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: zebrafish, heart regeneration, epicardium, perivascular cells, coronary vessels, scxa, hypoxia, collagen, Weill Cornell Medicine, Nature Communications, cardiac progenitor cells, vascular development