The Heart Pays the Price: How Cancer Drugs Disrupt Blood Vessel Sensing

by Amanda Chase, PhD
December 17, 2025

When Cancer Drugs Break the Heart’s Vascular Sensor

Targeted cancer therapies known as tyrosine kinase inhibitors (TKIs) have transformed cancer care. By blocking specific pathways that drive tumor growth, these drugs have extended survival for many patients. However, an important challenge has emerged: TKIs can also increase the risk of cardiovascular disease. Many patients treated with TKIs develop high blood pressure (hypertension), heart failure, or abnormal heart rhythms. These cardiovascular complications are not minor side effects. Persistent hypertension strains the heart and blood vessels, increasing the risk of heart failure and stroke. Heart failure reduces the heart’s ability to pump blood efficiently, leading to fatigue, shortness of breath, and reduced quality of life. Arrhythmias can disrupt normal heart rhythm and, in severe cases, become life-threatening. Together, these complications can limit how long patients can safely remain on otherwise life-saving cancer therapies. Despite how common and disruptive these problems are, very little has been known about the biological mechanisms behind TKI-related heart damage, making it difficult to design strategies that protect the heart without interfering with cancer treatment.

The Endothelium: A Hidden Player in Heart Health

A recent study published in Science Translational Medicine by researchers at the Stanford Cardiovascular Institute set out to determine whether damage to the endothelium, the thin layer of cells lining all blood vessels, plays a central role in TKI-associated heart disease. Endothelial cells are not passive bystanders. They actively regulate vascular tone by balancing when blood vessels relax (vasodilation) or tighten (vasoconstriction). This balance is critical for controlling blood pressure and ensuring healthy blood flow to the heart and other organs. When endothelial function is disrupted, blood pressure rises and the heart is forced to work harder over time.

Studying Cancer Drug Effects Using Patient-Specific Cardiovascular Cells

The research team, led by first authors Amit Manhas and Yu Liu and senior author Nazish Sayed, used patient-specific induced stem cell-derived endothelial cells (iPSC-ECs) to directly study how TKIs affect human blood vessels. These cells were generated from patients treated with TKIs, allowing the researchers to examine drug effects in a human-relevant vascular system. To understand how these vascular changes impact the heart over time, the team complemented these studies with a mouse model of TKI-induced cardiotoxicity and with engineered human cardiac organoids, 3D heart tissues that recreate key features of heart muscle and blood vessel interactions.

A Common Cancer Drug Disrupts Blood Flow Sensing

The study focused on sunitinib, a widely used TKI that targets the vascular endothelial growth factor receptor (VEGFR). VEGFR signaling is critical for blood vessel growth, which tumors rely on to survive. Blocking this pathway slows cancer progression, but it also affects normal blood vessel function. The researchers found that sunitinib disrupted a critical endothelial process known as mechanotransduction: the ability of blood vessels to sense and respond to the physical forces generated by flowing blood. A central player in this process is PIEZO1, a mechanosensitive ion channel that acts as a biological sensor. PIEZO1 allows endothelial cells to detect shear stress from blood flow and convert that mechanical signal into cellular responses that maintain vascular health and regulate blood pressure. 

Restoring Vascular Sensing Protects the Heart

Using advanced genetic and pharmacologic approaches, the researchers demonstrated that restoring PIEZO1 activity preserved blood vessels function and protected the heart in the presence of sunitinib. In engineered human heart tissue, they further showed that heart muscle cells were damaged only when endothelial cells were dysfunctional, highlighting the importance of communication between blood vessels and the heart muscle.

Toward Safer Cancer Therapies

Together, these findings identify disruption of endothelial mechanotransduction through PIEZO1 as a central driver of sunitinib-induced cardiovascular injury. The work provides a clear biological explanation for why this cancer drug can harm the heart and why these effects may persist even after treatment ends. Importantly, the study also points to a promising new strategy: protecting vascular health to reduce cardiovascular side effects during cancer therapy. By targeting the endothelium, it may be possible to allow patients to benefit from effective cancer treatment while safeguarding long-term heart health. “This work highlights the endothelium as a critical mediator of cancer therapy-related cardiovascular disease,” said senior author Nazish Sayed. “Understanding how these therapies affect blood vessels opens the door to new approaches for protecting the heart without compromising cancer care.”

Other Stanford Cardiovascular Institute authors include Chikage Noishiki, David Wu, Dipti Tripathi, Sarah Mirza, Dilip Thomas, Lu Liu, Patricia Nguyen, Ian Chen, Paul Cheng, Karim Sallam, and Joseph Wu. Melinda Telli from Stanford University was also part of the research team. Stanford researchers were joined by investigators at Medical College of Georgia at Augusta University (Avirup Guha), Boston University School of Medicine (Vipul Chitalia), and Rutgers New Jersey Medical School (Danish Sayed).