Mechanobiological regulation of ventricular maturation - gestationally survivable but clinically serious ventricular malformations (VM) exhibit MIS-sized ventricles, MIS- proportioned compact and/or…

The National Institutes of Health National Heart, Lung, and Blood Institute awarded Cornell University $734,475 on August 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate mechanobiological regulation of ventricular maturation.

The research will test the hypothesis that local mechanical stress operates a Piezo-Notch-YAP mechanobiological switch governing temporal compact and trabecular ventricular wall growth versus structural maturation dynamics. The work addresses ventricular malformations that exhibit mis-sized ventricles, mis-proportioned compact and/or trabecular myocardium, and impaired contractile function. Fewer than 20 percent of clinically diagnosed ventricular malformations have an identifiable genetic cause, underscoring the importance of understanding how hemodynamic loading shapes fetal and embryonic ventricular development. The project will apply partial atrial ligation to embryonic chick models to induce mechanical gain and loss of function in left and right ventricles, then quantitatively register local cellular composition, Notch-YAP activity, and tissue stress using computational fluid-structure simulations to map how heterogeneous cellular phenotypes and their neighborhood compositions change with hemodynamic perturbation and associate with structural malformation and clinically challenging pathologies such as hypoplastic left heart syndrome.

Work is performed at Ithaca, New York. The project extends from August 1, 2026, through April 30, 2030. Cornell University's Office of Sponsored Programs administers the award as a tax-exempt educational institution and land-grant university.

Mechanobiological regulation of ventricular maturation - gestationally survivable but clinically serious ventricular malformations (VM) exhibit MIS-sized ventricles, MIS- proportioned compact and/or trabecular myocardium, and/or impaired contractile function. Less than 20% of clinically diagnosed VM have an identifiable genetic cause. These findings emphasize the importance of conditional signaling between cells and their microenvironment to grow and mature ventricular structure for life- long function. Perturbation of hemodynamic loading in the embryonic heart is sufficient to generate clinically relevant ventricular malformations. While local fluid shear stress on the endocardium is critical for the initiation of trabeculation from the primary myocardium, far less is known about the mechanobiological mechanisms governing the clinically relevant fetal stages of myocardial compaction and trabecular expansion. If these rules were properly understood, scientists would gain substantial translatable leverage for diagnosing and counteracting malformation tendencies via alteration of local mechanobiological cues. Heterogeneous cellular phenotypes in ventricles change both in local proportion and differentiation state with fetal age. These neighborhood compositions and fates change with hemodynamic perturbation, associating with structural malformation and initiating clinically challenging ventricular pathologies such as hypoplastic left heart syndrome (hlhs). This proposal will test the central hypothesis that local mechanical stress operates a piezo-notch-YAP mechanobiological switch to govern temporal compact and trabecular ventricular wall growth VS. Structural maturation dynamics. Partial atrial ligation will be applied to embryonic chick to induce mechanical gain and loss of function in the left and right ventricles (aim 1), and quantitatively register local cellular composition, notch- YAP activity, and tissue stress using computational fluid-structure simulations and novel single-cell and spatial transcriptomics supported by bioinformatics analysis. Novel live cardiac slice cultures will be implemented to quantitatively map cellular velocities and forces within morphing fetal ventricles for the first time, and test notch- YAP gain/loss of function mechanisms of cellular kinematics driving morphing decisions (aim 2). Aim 3 will test how pharmacological reactivation of mechanobiological signaling in depressed hemodynamic environments can restore ventricular growth in vivo. These results will define the engineering system by which heterogeneous cellular communities engage local mechanical signaling to drive ventricular compact VS. Trabecular growth, remodeling, and maturation. These findings will clarify confusion in the field and inform strategies to counteract ventricular malformation in vivo.