Lab Research Interests

The UCSF Laboratory of Molecular Cardiology is directed by Dr. Matthew L. Springer and is closely associated with Dr. William Grossman and Dr. Kanu Chatterjee.  Our research benefits greatly from long-term collaborations with Dr. Randall J. Lee and Dr. Yerem Yeghiazarians.  Our current studies reflect our interests in both basic and applied preclinical research.

Major interests:

Angiogenesis
Cell therapy for myocardial infarction
Role of NO synthase in endothelial progenitor cell function
Endothelium-dependent vascular reactivity


Angiogenesis 

We are studying differential responses of adult cardiac and skeletal muscle to angiogenic gene therapy, focusing on effects of VEGF and pleiotrophin on the vasculature and on the localized protein profile in the tissue.  This continues a decade of Dr. Springer's research aimed at understanding the response of adult tissue to exogenous VEGF gene delivery, potential deleterious effects, and potential therapeutic applications. 

Using virally-transduced myoblasts as a gene delivery vehicle, this research has demonstrated that VEGF expression can induce vascular growth in both ischemic and non-ischemic mouse skeletal muscle and myocardium.  The newly-formed capillaries are in contact with the circulation, and new arterioles form upstream of the capillaries.  Interestingly, the vascular response is extremely localized within micrometers of the VEGF source through a heparin-independent mechanism.

Notably, constitutive expression of excessive amounts of VEGF causes vascular overgrowth, leading to vascular malformations and hemangiomas in both skeletal and cardiac muscle.  In skeletal muscle, this effect occurs even if excessive levels are produced in only small regions of the tissue, and Dr. Springer's former colleagues have shown that implantation of homogenous populations of these myoblasts in which every cell expresses moderate levels of VEGF leads to growth of non-pathological, stable vessels that increase perfusion to ischemic regions. 

We are continuing this line of research in the heart to determine if such exquisite dose response and microenvironmental control determine vessel growth pattern and morphology in cardiac muscle, to evaluate the impact of these properties on cardiac function after myocardial infarction, and to determine differences in molecular responses of skeletal and cardiac muscle to VEGF gene delivery.                                                            


Cell therapy for myocardial infarction 

In collaboration with Dr. Yeghiazarians, we are studying the therapeutic effects of implanting bone marrow-derived cells (BMCs) into mouse hearts after myocardial infarction (MI), using a high-resolution echocardiography approach that our collaboration has developed to guide injections into the myocardial wall without surgery.  Our study includes evaluation of the clinical relevance of common rodent models used for such experiments, and of approaches to overcome the limitations of these models to represent realistic cardiovascular disease and treatment. 

The echo-guided approach allows us to introduce BMCs to mice several days after MI, a time relevant to current clinical trials that is not feasible when using traditional open-chest injection approaches.  We have shown that injection of BMCs 3 days post-MI can preserve or partially restore left ventricular function.  We have also demonstrated that injection of a cell-free extract of lysed BMCs has a similar therapeutic effect, suggesting not only that BMC therapy may be beneficial by a paracrine mechanism, but also that the cells may simply die and thus deliver a bolus of therapeutic growth factors. 
                                                                                                                          

Role of NO synthase in human endothelial progenitor cell function 

A related project is aimed at understanding the molecular basis of age- and disease-related impairment of endothelial progenitor cells (EPCs), a heterogeneous population of cells that are thought to be involved in several aspects of angiogenesis and endothelial maintenance. 

We are studying endothelial nitric oxide synthase (eNOS)-dependent and eNOS-independent mechanisms of EPC migration toward angiogenic stimuli by VEGF and pleiotrophin, and are investigating the molecular mechanisms through which NO controls EPC migration and differentiation.  We are also investigating the correlation between eNOS activity and EPC function both ex vivo and in vivo, including the genetic manipulation of these cells to enhance or impair their functional profile. 
                                                                                                                          

Endothelium-dependent vascular reactivity 

We have developed an ultrasound-based approach to measure flow-mediated vasodilation (FMD) in arteries of living rats, and have shown that FMD in the rat model is physiologically similar to that in humans.  The vasodilation that occurs after transient upstream arterial occlusion is dependent on hyperemic blood flow and is also dependent on eNOS activity.  We have been able to detect age-related impairment of FMD with this approach. 

We are currently using this system to study mechanisms underlying endothelium-dependent vascular reactivity, as well as the beneficial and deleterious effects of dietary flavanols and environmental tobacco smoke on vascular function.