Studies in the Caron laboratory have been focused on defining the normal and pathological functions of a small blood protein, called adrenomedullin, which has been broadly implicated in a wide variety of biological processes and human diseases. We have used sophisticated gene targeting strategies to develop animal models that have either increases or decreases in adrenomedullin dosage or genetic deficiencies in the G-protein coupled receptor (GPCR) and receptor activity modifying proteins (RAMPs) that transduce adrenomedullin signaling. Because the GPCR-RAMP interaction provides a unique and pharmacologically tractable interface for novel drug design, it is not surprising that many research laboratories and the pharmaceutical industry are hoping to exploit adrenomedullin and its receptors for the pharmacological treatment of disease. Our work thus far in animal models has helped to define the biological functions of adrenomedullin under normal and pathological conditions and has provided fundamental insights into the mechanisms that underlie several common and severe cardiovascular disorders.
Major focus areas within the field of cardiovascular biology include:
1. Gender-Dependant Mechanisms of Cardioprotection
Adrenomedullin and its receptors are highly expressed in endothelial cells and vascular smooth muscle cells and provide beneficial cardioprotective effects to the heart, kidneys and vasculature. Using a variety of gene targeted animal models we have demonstrated that the cardioprotective effects of adrenomedullin are highly dependant on genetic dosage and gender. Since bolus infusions of adrenomedullin can counteract organ damage following myocardial infraction, studies to determine how these cardioprotective effects are mediated and whether they may vary by gender are of substantial clinical importance.
2. Lymphatic Vascular Biology
A second major emphasis area is to define the function of adrenomedullin signaling in lymphatic endothelial cells. Mice with targeted null mutations in adrenomedullin, its GPCR CLR or RAMP2 die at mid-gestation with hydrops fetalis associated with defects in the development of the lymphatic vascular system. Expression of CLR and RAMP2 is potently up-regulated in lymphatic endothelial cells and adrenomedullin can regulate both the permeability and proliferation of cultured lymphatic endothelial cells. Since adrenomedullin and its receptors represent one of the few pharmacologically tractable factors for lymphatic endothelial cells, we are interested in using our genetic mouse models to determine whether modulation of adrenomedullin signaling can affect lymphatic permeability or proliferation in vivo. If we are correct, then adrenomedullin-based therapies may eventually become useful for the treatment of lymphatic-based conditions such as lymphedema or tumor metastasis.
3. Establishing and Maintaining the Maternal-Fetal Interface
Plasma levels of adrenomedullin rise dramatically during the course of a normal pregnancy, but are often blunted in pregnancies with complications. We have shown that female mice with a modest 50% reduction in adrenomedullin gene expression suffer from subfertility due to a variety of reproductive defects including abnormal uterine receptivity, implantation and placentation. Moreover, loss of adrenomedullin from fetal tissues leads to pathological symptoms of preeclampsia in the placenta. Therefore, the precise genetic dosage of adrenomedullin, both from the mother and the fetus, is crucial for establishing and maintaining a normal pregnancy. We are currently investigating the underlying mechanistic basis for the reproductive defects, with a particular focus on the potential role of adrenomedullin as a modulator of the innate immune response at the maternal-fetal interface.