How Developmental “Memory” Shapes the Arteries,
and the Diseases They Face

by Amanda Chase, PhD
December 15, 2025

Every artery in the human body looks roughly the same under a microscope: strong, flexible tubes that carry blood under pressure to every organ. Yet for reasons that have long puzzled physicians, some arteries are far more prone to disease than others. The coronary and carotid arteries, for instance, often develop atherosclerosis, while neighboring segments of the aorta remain relatively unscathed. Aneurysms, meanwhile, tend to appear in completely different places.

Two recent studies from Stanford University and Cardiovascular Institute members have begun to explain this mystery by revealing that each arterial segment carries a molecular fingerprint of where it came from during embryonic development, and that this “memory” continues to shape its biology, and even its vulnerability to disease.

Building an Atlas of the Human Arterial Wall

The first study was recently published in Cell Genomics, led by first authors Quanyi Zhao, Albert Pedroza, and Disha Sharma, as well as senior authors Paul Cheng and Thomas Quertermous. The research team created an unprecedented single-cell and spatial atlas of the human arterial vasculature. Working with organ-donor tissue from nine major arterial sites, from the aortic root to the iliac and pulmonary arteries, the team used single-cell RNA sequencing and spatial transcriptomics to map nearly 200,000 cells. They identified every major cell type that comprises the arterial wall, including smooth muscle cells, fibroblasts, endothelial cells, and resident immune cells.

Zhao et al., Cell Genomics, created a single-cell and spatial atlas of the human arterial vasculature, mapping nearly 200,000 cells. They used advanced techniques to identify cell types that make up the arterial wall and the gene expression program within those cells

What they found was striking. Although the general architecture of arteries was consistent, the gene-expression programs within those cells varied dramatically from one vascular region to another. Two particular cell types, smooth-muscle cells (SMCs) and adventitial fibroblasts, showed the greatest differences. Their transcriptomes carried distinct “signatures” that correlated not with the physical location of the artery, but with its embryonic origin.

Cells in the upper aorta and coronary arteries, derived from the neural crest and second heart field, expressed a different set of developmental genes than those in the descending or iliac arteries, which arise from mesodermal tissue. The researchers could essentially read the developmental ancestry of an artery from the pattern of genes still active in its adult cells.

This developmental coding aligned with the very regions known to harbor disease. The fibroblasts from neural-crest-derived segments were enriched for genes associated with aortic aneurysm syndromes, such as FBN1 and TGFBR2, whereas SMCs from other sites expressed genes linked to atherosclerosis or fibrotic remodeling. Even non-coding RNAs, once thought to be molecular noise, showed region-specific patterns that coincided with genetic risk loci for vascular disease.

Taken together, the findings suggested that adult arteries retain a molecular imprint of their origin, and that imprint may predetermine how each region responds to stress, injury, or inflammation.

The Epigenomic Blueprint

While the Zhao et al. study charted gene activity, it did not explain why those patterns persist. The second study, led by first author Chad Weldy and senior author Thomas Quertermous, turned to the epigenome, the layer of chromatin architecture that determines which genes are accessible for transcription.

In their work, published in Molecular Systems Biology, the team performed single-cell ATAC-seq alongside single-cell RNA-seq on three distinct regions of healthy mouse aorta: the ascending aorta, carotid artery, and descending thoracic aorta. This dual approach allowed them to see which genes were turned on and which sections of DNA were physically “open” or “closed” to the transcriptional machinery.

The results mirrored and extended the human atlas. Even in healthy mice, each vascular site displayed a unique pattern of chromatin accessibility, a site-specific enhancer landscape that corresponded to its developmental lineage. In smooth-muscle and fibroblast cells, enhancers near classic developmental transcription-factor genes such as HAND2, GATA4, and TBX20 were active in the ascending aorta and carotid artery, whereas HOX and MEF2A motifs predominated in the descending aorta. By integrating genome-wide genetic data with enhancer maps, the researchers found that genetic variation influences vascular disease risk in both a cell-type-specific and vascular-site-specific manner. This was a previously unrecognized finding, and a key, innovative finding of this study. Using computational models, the researchers were also able to predict how genetic variants within these enhancers might alter chromatin accessibility and influence human disease risk.

Weldy et al, Molecular Systems Biology, used single-cell epigenomic profiling to see where genes were turned on. They also used machine learning in a unique approach, finding that genetic variation influences vascular disease risk is cell-type- and vascular-site-specific.

These site-specific enhancer maps provided an epigenetic explanation for the transcriptional diversity observed in the human study. The developmental origin of an artery imprints a stable chromatin pattern that continues to guide how its cells interpret signals decades later.

Two Layers of the Same Story

Viewed together, the human and mouse studies form a seamless continuum, spanning from gene expression to chromatin regulation, and from embryonic development to adult disease. Zhao et al. described the transcriptomic identity of vascular cells across the human body, revealing where developmental programs remain active. Weldy et al. showed how those identities are encoded at the epigenomic level and tied to specific enhancer regions and transcription factor motifs.

These collaborative, multi-disciplinary projects were featured on the cover of Cell Genomics and Molecular Systems Biology.

Both converge on the idea that the arterial system is not uniform but a collection of subtly distinct “micro-organs,” each programmed during embryogenesis to respond differently to the same stressors. A force or signal might trigger protective pathways in one segment but pathogenic ones in another. This suggests that disease patterns follow developmental blueprints, and that understanding those blueprints could guide personalized prevention and therapy. This also creates the possibility that therapies could be tailored to the unique molecular contexts. Further, integrating genome-wide association data with single-cell maps could help determine which genetic variants exert their effects

in which vascular areas, clarifying why the same mutation can predispose one person to, for example, a thoracic aneurysm but another individual to coronary disease.

These discoveries were only possible because of the collaborative environment at the Stanford Cardiovascular Institute, where researchers and clinicians from different areas come together to collaborate on critical cardiovascular health issues. Stanford’s status as one of the largest heart transplant centers in the US, and the unique research focus of the Cardiothoracic Surgery Department, allowed the team to obtain human tissue of exceptional quality. This tight integration between clinical and research teams provided researchers with a unique window into what cells make up the human arterial system. The infrastructure and interdisciplinary community at CVI allowed researchers from cardiothoracic surgery, cardiology, and genetics to come together to share their ideas, innovative tools, and unique resources. By uniting strengths, this multidisciplinary team reached a level of insight that could only come from true interdisciplinary collaboration.

These projects showcase the power of collaboration and multi-disciplinary work and are the result of the contributions of many other authors. Other Stanford authors involved in the Zhao et al. Cell Genomics manuscript include Wenduo Gu, Alex Dalal, Chad Weldy, William Jackson, Daniel Yuhang Li, Yana Ryan, Trieu Nguyen, Rohan Shad, Brian T. Palmisano, João P. Monteiro, Matthew Worssam, Alexa Berezwitz, Meghana Iyer, Huitong Shi, Ramendra Kundu, Lasemahang Limbu, Juyong Brian Kim, Anshul Kundaje, and Michael Fischbein. Other Stanford authors involved in the Weldy et al. Molecular Systems Biology includes Soumya Kundu, João Monteiro, Wenduo Gu, Albert J Pedroza, Alex R Dalal, Matthew D. Worssam, Daniel Li, Brian Palmisano, Quanyi Zhao, Disha Sharma, Trieu Nguyen, Ramendra Kundu, Michael Fischbein, Jesse Engreitz, Anshul Kundaje, and Paul Cheng.