Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with multisystem organ dysfunction, including symptoms of heart failure (HF) together with macro and micro vasculopathy, pulmonary, renal, and metabolic abnormalities. Unique to HFpEF is preservation of myocardial contractility (left ventricular ejection fraction > 50%), although HFpEF patients also have evident diastolic dysfunction. The importance of recognizing the pathophysiological mechanisms of HFpEF is increasingly acknowledged.
Pulmonary hypertension (PH) is a severe form of pulmonary vascular disease that results in death of up to two-thirds of affected patients within five years of diagnosis. Group 3 PH, due to hypoxia, increases the morbidity and mortality of patients with bronchopulmonary dysplasia (BPD) and chronic obstructive lung disease (COPD). A mechanistic understanding of the pulmonary vascular remodeling that occurs in Group 3 PH is necessary to help identify non-invasive diagnostic tools for early detection of cardiopulmonary compromise and to develop new targeted therapies that are effective in this class of PH.
Fibroblast growth factor (FGF) signaling is important for cardiovascular development, homeostasis, and injury response. In vascular smooth muscle (VSM), FGF and TGFβ signaling are implicated in directing the VSM phenotype from a “proliferative (immature)” to a “contractile (mature)” state in the context of atherosclerosis. Interestingly, FGF signaling inhibits TGFβ activity and promotes a VSM proliferative phenotype, a phenomenon that was demonstrated in our published transcriptomic data.
We have shown that FGF signaling is important for the VSM response to cardiovascular stress caused by administration of Angiotensin II and Phenylephrine (AngII/PE) infusion (HFpEF model) or hypoxia (Group 3 PH model). In mice that conditionally inactivate FGF receptor 1 (Fgfr1) and Fgfr2 in VSM, we find significantly reduced vascular thickening and perivascular fibrosis following infusion of AngII/PE, but increased vascular muscularization in response to hypoxia. Using mouse genetic models and human VSM cell culture, we are investigating the mechanisms by which FGF signaling regulates VSM remodeling in response to stress or injury.
Cardiovascular publications:
1. Cilvik, S.N., Wang, J.I., Lavine, K.J., Uchida, K., Castro, A., Gierasch, C.M., Weinheimer, C.J., House, S.L., Kovacs, A., Nichols, C.G., and Ornitz, D.M. (2013). Fibroblast growth factor receptor 1 signaling in adult cardiomyocytes increases contractility and results in a hypertrophic cardiomyopathy. PLoS One 8, e82979. 10.1371/journal.pone.0082979.
2. Oladipupo, S.S., Smith, C., Santeford, A., Park, C., Sene, A., Wiley, L.A., Osei-Owusu, P., Hsu, J., Zapata, N., Liu, F., et al. (2014). Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A 111, 13379-13384. 10.1073/pnas.1324235111.
3. House, S.L., Castro, A.M., Lupu, T.S., Weinheimer, C., Smith, C., Kovacs, A., and Ornitz, D.M. (2016). Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 310, H559-571. 10.1152/ajpheart.00758.2015.
4. Woo, K.V., Ornitz, D.M., and Singh, G.K. (2019). Diagnosis and Pathophysiological Mechanisms of Group 3 Hypoxia-Induced Pulmonary Hypertension. Curr Treat Options Cardiovasc Med 21, 16. 10.1007/s11936-019-0718-3.
5. Woo, K.V., Shen, I.Y., Weinheimer, C.J., Kovacs, A., Nigro, J., Lin, C.Y., Chakinala, M., Byers, D.E., and Ornitz, D.M. (2021). Endothelial FGF signaling is protective in hypoxia-induced pulmonary hypertension. J Clin Invest 131. 10.1172/JCI141467.
6. Matsiukevich, D., House, S.L., Weinheimer, C., Kovacs, A., and Ornitz, D.M. (2022). Fibroblast growth factor receptor signaling in cardiomyocytes is protective in the acute phase following ischemia-reperfusion injury. Front Cardiovasc Med 9, 1011167. 10.3389/fcvm.2022.1011167.
7. Matsiukevich, D., Kovacs, A., Li, T., Kokkonen-Simon, K., Matkovich, S.J., Oladipupo, S.S., and Ornitz, D.M. (2023). Characterization of a robust mouse model of heart failure with preserved ejection fraction. Am J Physiol Heart Circ Physiol 325, H203-H231. 10.1152/ajpheart.00038.2023.