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Dr. Michael Simons, Section of Cardiovascular Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520
The development of new biological therapeutics such as neutralizing antibodies and small molecule inhibitors of receptors signaling is revolutionizing many fields of medicine—and creating new insights into normal biology. In particular, inhibition of blood vessel growth has been vigorously pursued in a number of fields, including oncology and ophthalmology. To date, most experience with this class of drugs centers on anti-vascular endothelial growth factor (VEGF) agents such as a neutralizing antibody bevacizumab and small molecule inhibitors of VEGF receptor-2 (VEGFR2). Anti-VEGF therapies have been spectacularly successful for treatment of macular degeneration, and somewhat less so in the treatment of cancer. Hand in hand with these advances is the emergence of new cardiac illnesses directly related to the activity of these agents.
VEGF is thought to play a key role in blood vessel development. Vascular growth is so exquisitely VEGF dependent that even a single copy deletion of the VEGF gene itself, or of other genes in its signaling pathway, results in early embryonic lethality (1,2). VEGF is also involved in blood vessel growth in pathological states such as a “wet form” of macular degeneration and growth of the tumor vasculature, normal tissue repair processes such as wound healing, and normal physiological events such as vasculature growth in the uterus during the menstrual cycle (3).
Although these VEGF functions are well recognized, until recently there has been little information about what VEGF does in the normal adult vasculature. Some hints came from studies of pre-eclampsia in which increased circulation of VEGF “traps” such as a circulating form of VEGF receptor-1 (4) have been associated with decreased VEGF bioavailability and increased blood pressure. Other hints came from clinical trials of bevacizumab, where frequent incidence of hypertension was noted. A recent meta-analysis of trials enrolling 12,656 patients shows that the therapy is associated with a 23.6% incidence of all-grade and a 7.9% incidence of high-grade hypertension. Other cardiovascular toxicities linked to anti-VEGF therapies include increased risk of congestive heart failure, proteinuria, arterial thromboembolic events, and hemorrhage (5).
This panoply of complications provides compelling evidence for an important role played by VEGF in the maintenance of the normal vasculature. Although much effort over the last 2 decades has gone into anti- and pro-angiogenic therapies, the very concept that a normal vasculature needs to be actively “maintained” is new. Endothelium is subjected to physical forces, such as shear and circumferential stresses, and to a variety of hormones, cytokines, and growth factors. In its own right, the endothelium is also an active endocrine organ that secretes numerous cytokines and growth factors, and it engages in complex interactions with nonvascular cells that affect functions of many organs, including the heart, brain, kidneys, and liver. Such a busy life and heavy exposure to stressors can be easily imagined to lead to injury requiring replacement. Yet data from numerous laboratories show very low basal level of endothelial cell proliferation in the normal vasculature. In the absence of ongoing replacement, maintenance of the existing endothelial cell stock takes on an even larger importance.
Recent studies in mice have shown that withdrawal of VEGF (6), and surprisingly, fibroblast growth factors (7), can lead to deleterious alterations in the normal vascular function and profound systemic consequences. The study by Belcik et al. (8) in this issue of the Journal adds an important element to our understanding of the role of VEGF in the normal vasculature. The authors find that systemic therapy with an anti-VEGF antibody in mice leads to increased blood pressure, myocardial hypertrophy, and renal abnormalities, thus mimicking many side effects seen in clinical trials.
Multiple theories have been advanced to explain increased blood pressure following administration of systemic anti-VEGF or VEGFR2 therapies. These include microvascular rarefication (implying a decrease in vascular capacity), increased arterial stiffness, reduction in nitric oxide (NO) production, and increased expression of pro-hypertensive agents such as endothelin-1. Belcik et al. convincingly show that a substantial hypertensive response induced by a 5-week course of anti-VEGF antibody therapy is clearly not due to changes in arterial stiffness. The authors also found no evidence for a decrease in microvascular volume, but the technique used for its assessment, contrast-enhanced ultrasound, may lack the sensitivity to detect small volume changes. Nevertheless, it seems unlikely that a capillary rarefication, unless very pronounced, would affect systemic blood pressure. Perhaps the most interesting observation is an increase in angiotensin II (Ang II) levels and the improvement in blood pressure after ramipril treatment. The increase in Ang II levels in this setting has not been previously reported even though renal abnormalities, including thrombotic microangiopathy, have been observed in patients and in animal models of anti-VEGF therapy.
An important limitation of this study is the absence of assessment of NO production. Endothelium is the major source of NO under noninflammatory conditions, with eNOS (NOS3) being the principle enzyme responsible for its generation. VEGF is known to control eNOS expression, and it is certainly plausible that its absence may result in decreased eNOS levels and/or reduced activation. Consistent with this idea of partial eNOS suppression is the fact that an eNOS gene knockout results in a more severe increase in blood pressure than was observed in this study. Unfortunately, eNOS dysfunction has never been conclusively demonstrated in a VEGF deficiency setting. In the current study, anti-VEGF treatment was associated with reduced eNOS expression, whereas levels of activated eNOS remained unchanged, suggesting, but not conclusively demonstrating, no reduction in overall NO production.
In addition to hypertension, a number of other complications can arise due to VEGF absence. VEGF is required for maintenance of glomerular podocytes, and their loss results in the albuminuria observed with anti-VEGF agents (9). In the central nervous system, VEGF absence has been linked to depression (10). In the heart, VEGF plays a major role in coupling coronary circulation to myocardial function. Afterload-induced myocardial hypertrophy requires concomitant VEGF-driven coronary angiogenesis to maintain myocardial perfusion (11), whereas expansion of the coronary vasculature can induce myocardial hypertrophy even in the absence of a physical stimulus (12). Myocardial dysfunction observed in the present study and in the settings of anti-VEGF therapy is likely the result of disruption of this balance.
Finally, it is interesting to draw a parallel between the now-emerging field of cardio-oncology and the field of restenosis in the 1990s. The emergence of restenosis, essentially a new disease brought about by the development of intravascular devices, as an important clinical problem became the catalyst for an unprecedented growth of cardiovascular molecular biology. This not only led to the discovery of treatment for restenosis, but equally importantly, broadened the scope of traditional cardiovascular research, brought new minds and new technologies into the field, facilitated the development of many new therapies, and in the process, put molecular cardiovascular research on an equal footing with such fields as endocrinology and oncology, which transitioned to molecular cell biology earlier than cardiology. Now the introduction of new types of biologics into cancer treatment protocols has led to the appearance of new cardiovascular diseases that can be traced, not to “off-target” effects of these drugs, but very much to their “on-target” activity. This will undoubtedly lead to a new surge of interest in basic cardiovascular biology, bring new minds and technologies to the field, and will further advance science and medicine. A larger picture is that these 2 paradigms show how translational research frequently works in real life—a therapeutic advance that leads to a new and unexpected complication that in turn requires deeper understanding of biology that can be then used to solve new clinical problems.
Supported in part by the National Institutes of Health grant HL53793 (to Dr. Simons) and ARTEMIS Foundation Leducq Transatlantic Network grant (to Drs. Simons and Eichmann).
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
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