Muscle injuries are one of the most common pathologies in orthopedic practice. Most muscle injuries (10% to 55% of all injuries) occur during sports activities. Muscle injuries are a serious problem due to slow recovery, during which athletes are unable to participate in training and competition, as well as due to the frequent consequences and recurrence of injuries [6]. Muscle regeneration is a complex biological process. Once damaged, satellite cells proliferate, thus providing enough cells for repair. The proliferation phase ends with the appearance of the first small regenerating muscle tubes approximately 3 days after injury [7]. At the same time, some of the proliferated cells become immobile again, while the rest begin to merge with the formation of multinucleated muscular tubes (terminal differentiation). Subsequently, there is a biochemical differentiation of muscle tubes into muscle fibers. This process is accompanied by an increase in macrophages and the destruction of damaged fibers. The results obtained when studying the effect of VEGF-A on the formation of myotubes show that this process is associated with the stimulation of differentiation by increasing the maturation of multinucleated myofibrils [8]. To identify the receptor that mediates these effects of VEGF-A on myogenic cells, it must be kept in mind that both VEGFR-1 and VEGFR-2 are activated in differentiating myogenic cells, in myotubes, and in satellite cells after muscle injury. In cultured myoblasts and cells, inhibition of the VEGFR-2 protein kinase reverses the protective effect of VEGF-A on cell apoptosis, suggesting the involvement of VEGFR-2 in mediating VEGF-A signal. The effect of VEGF-A on muscle recovery after injury is likely to be mediated by various mechanisms. The factor has a well-known proangiogenic activity; research results show [9,10] that it prevents apoptosis and promotes muscle fiber growth. According to the authors, the restoration of muscle tissue is realized through the interaction of all the listed effects of VEGF-A. An additional possibility is that mobilizing bone marrow progenitor cells, VEGF-A promotes muscle regeneration through transdifferentiation or fusion of these cells, although there is evidence to refute this mechanism. For a long time, VEGF-A was considered an endothelial-specific growth factor that promotes a strong angiogenic response. However, current studies demonstrate the ability of VEGF-A to induce myofibril regeneration in skeletal muscle. In addition to angiogenesis, the interaction of VEGF-A with its receptors is important for the survival and stimulation of cell differentiation in a wide range of different tissues, including skeletal muscle [8].

Studies by many authors have shown that physical activity has a positive effect on the coronary vasculature, including myocardial oxygen demand, endothelial function, autonomic tone, markers of inflammation, and the development of collateral coronary vessels [11,12]. However, the direct effect of exercise on myocardial angiogenesis remains poorly understood. Physical activity is accompanied by functional, electrical, and structural remodeling of the heart. Myocardial hypertrophy is accompanied by an increase in the left atrium diameter, the left ventricle wall thickness, and myocardial mass. Vascular changes in the myocardium are reported to be associated with neoangiogenesis and capillary density in the heart muscle [13]. Angiogenesis in the myocardium is a complex process mediated by the interaction of proangiogenic and anti-angiogenic factors. Cardiomyocytes express VEGFR-1 and VEGFR-2, which are rapidly activated in response to hypoxia [14]. It is believed that the role of VEGF-A in myocardial remodeling is related to the balance of its actions on VEGFR-1, which inhibits the development of hypertrophy, and VEGFR-2, which has prohypertrophic effects. A transgenic murine model of VEGFR-1 deletion of endothelial cells led to angiogenesis and the development of cardiomyocyte hypertrophy through signaling of erb-B tyrosine kinase [15]. These processes can be further influenced by microRNAs (miRNAs) such as miR-374, which is known to positively regulate cardiomyocyte hypertrophy in murine models. Vascular endothelial growth factor-B (VEGF-B) and angiopoietin 1 (ANGPT-1) are the main angiogenic factors that enhance endothelial cell proliferation and accelerate vascular growth in the infarction zone [13]. Among the various types of mechanisms that regulate gene expression, epigenetic changes associated with the acetylation–deacetylation of histones by various isoforms of histone deacetylase (HDAC) are also important [16]. Recent research indicates that changes in oxidant/antioxidant balance can affect angiogenic activity in tissues [17]. These oxidative changes are the result of reactive oxygen species (ROS). ROS can change the structure of proteins, lipids, carbohydrates, and nucleic acids. According to the authors, damage to the mitochondrial membrane is realized through ROS radicals derived from xanthine oxidase of inflammatory cells [ibid.]. Alternatively, during oxidation, the high rate of destruction of red blood cells from intense endurance exercise can increase the amount of free iron, which will help protect highly reactive hydroxyl radicals through iron-catalyzed Haber–Weiss reactions. Ardakanizade et al. [13] studied short-term and long-term adaptive changes occurring in the myocardium as a result of physical exertion on endurance to elucidate the molecular picture of tissue remodeling. In addition, the authors tried to reveal the effect of an exercise regimen on oxidative changes and angiogenesis in the heart muscle. Experimental studies conducted in animals showed high myocardial plasticity as a result of endurance exercises, which was expressed by changes in the signaling cascade at the level of transcription and translation. These changes increased the contractile ability of the myocardium, and consequently, the cardiovascular system potential [18]. A significant increase in myocardial contractility was accompanied by a significant increase in its mass and left ventricle wall thickness. The study reported the presence of the heart muscles impairment, which was accompanied by oxidative changes. The results showed that oxidative stress was dependent on the duration of endurance exercise. The decrease in antioxidant capacity was more pronounced with prolonged exercise, indicating an increase in oxidative changes caused by the duration of the exercise program. Oxidative changes have been expressed as an increase in oxidative markers (nitric oxide (NO)) and the end product of lipid peroxidation (MDA). With prolonged endurance exercise, vasodilation occurs due to the need for blood supply to the heart muscle. Therefore, NO is involved in blood supply, helping coronary arteries through endothelial nitric oxide synthase (eNOS) [19]. This blood supply is always accompanied by an increase in NO and the expression of the gene for vascular endothelial growth factor beta (VEGF-B) in the molecular structure.

VEGF-B becomes active due to the interaction between a hypoxia-inducible factor-1 (HIF-1) and a hypoxia reactive element (HRE) in response to hypoxia induced by prolonged endurance exercise [20,21]. VEGF-B stimulates endothelial cell proliferation as well as migration and new vessel formation through transmission signal carried out by tyrosine kinase receptors [22]. Thus, the need for blood supply to the coronary muscles is satisfied by the process of angiogenesis and expression of VEGF-B. As the expression of VEGF-B increased in the experimental group (performing endurance exercises for a long time), the same group demonstrated a higher level of angiogenesis. Thus, the higher production of ROS, which occurs concurrently with the higher expression of VEGF-B, confirms the relationship between angiogenesis and oxidative stress. Exercise induces muscle tissue calcineurin signaling pathways to enable muscle tissue contraction. It has been shown in the literature that the regulation of calcineurin-dependent genes is mediated by the MEF2 transcription factors [23]. Moreover, it was indicated that the expression of the MEF-2c gene can be increased in endothelial cells via VEGF-B, which, in turn, regulates the process of vasculogenesis [24]. Therefore, a significantly higher expression of the VEGF-B gene and the VEGF-B gene induced by endurance exercise is associated with an increase in cardiac muscle contractility and vascularization. Angiopoietin 1 (ANGPT-1) is a protein that supports the survival of endothelial cells during angiogenesis. VEGF-B-induced vascular permeability can be blocked and regulated by overexpression of ANGPT-1 [24]. Thus, the density of new vessels can be adjusted. Accordingly, a higher expression of ANGPT-1 in the experimental group (where endurance exercises were performed for a short period of time) contributed to the angiogenesis regulation. However, this was not observed in another study group with a longer period of endurance exercises [13]. This suggests that with prolonged aerobic loads, regulation of angiogenesis is impaired and new blood vessels are formed. These data are consistent with the results of other studies, which reported that concomitant expression of VEGF-B and angiopoietin-2 can increase and regulate the density and permeability of microvessels [25].

After birth, mammalian cardiomyocytes become differentiated and generally lose their ability to proliferate. However, a certain level of their renewal occurs throughout life [26]. Note that in adulthood, the growth of the heart occurs more due to hypertrophy of cardiomyocytes than due to hyperplasia. Myocardial hypertrophy can be either physiological or pathological. Physiological hypertrophy is the result of a response to exercise or other stimuli. Normally, a hypertrophied heart exhibits improved vascular perfusion and metabolism, and the growth process is initiated by molecular pathways specific for physiological hypertrophy [27]. Cardiac perfusion is largely controlled by the microvessel through a dense capillary network with approximately one capillary per muscle fiber. Consequently, being critical for neoangiogenesis, VEGF plays a central role in cardiomyocyte hypertrophy.

The role of VEGF-A in maintaining the “angiogenic switch” balance in the cardiovascular and cerebrovascular systems is beyond doubt. The positive effects of VEGF-A are associated with the protection of endothelial cells by increasing the expression level of antiapoptotic proteins and NO synthesis [28]. VEGF causes severe endothelium-dependent vasodilation, primarily through nitric oxide (NO) and prostacyclin (PGI2). In cultured human endothelial cells, binding of VEGF-A to VEGFR-2 activates the PI3K/Akt pathway, followed by activation of endothelial NO synthase (eNOS) and NO release. However, VEGF-induced vasodilation is not reversed by inhibition of NO and PGI2, suggesting that an endothelial-derived hyperpolarizing factor (EDHF) is also involved in VEGF-mediated vasodilation [29]. The negative effects of VEGF-A have been reported in several studies. The ability of VEGF-A to induce atherogenesis and its effect on endothelial cells as a mitogen through re-endothelialization were reviewed by Braile et al. [30]. The mitogenic effect of VEGF-A on endothelial cells is mediated through VEGFR-2 and the activation of kinase is regulated by extracellular signals (ERK1/2). Phosphorylation of VEGFR-2 leads to the activation of phospholipase C (PLC-γ), which in turn stimulates the Raf-MAPK/ERK (MEK)-ERK1/2 kinase cascade in cultured endothelial cells [29]. VEGF-A plays a role in cell migration, including vascular smooth muscle cells, monocytes, and polymorphonuclear cells. In endothelial cells, cell migration is induced by activation of focal adhesion kinase (FAK) and paxillin, as well as via the phosphatidylinositol kinase (PI3K)/Akt and MAPK pathways [29]. The ability of VEGF-A to induce adhesion of monocytes through transendothelial migration and activation [31], improving endothelial permeability and increasing expression of the adhesion protein and chemoattractant protein-1 of monocytes has also been described [32]. VEGF-A was previously known as a vascular permeability factor. Its interaction with VEGFR-2 on cultured endothelial cells triggers the activation of several pathways that regulate the adhesive properties of the transmembrane protein, vascular endothelial cadherin (VE-cadherin). These pathways include the protooncogene tyrosine kinase src and culminate in phosphorylation and internalization of VE-cadherin, separating it from the cytoskeleton. This subsequent loss of adhesive bond results in a marked increase in vascular permeability.

Ylä-Herttuala et al. found no VEGF-A or its receptors in intact segments of human coronary vessels. However, their expression increases in endothelial microcapillaries, in macrophages, and in partially differentiated smooth muscle cells of atherosclerotic lesions [33]. In their research on animal model of rabbits exposed to 8 weeks of chronic stress, Yu et al. revealed instability of atherosclerotic plaques and activation of angiogenesis caused by the release of VEGF-A which was found in large amounts in blood serum [34].

Sports loads in cyclic sports are associated with an increase in oxygen consumption. That is why the pulmonary system becomes the main system subject to functional changes during exercise. Numerous studies of the sports physiology have demonstrated a clear relationship between heart rate, oxygen consumption, respiratory rate and minute ventilation, energy metabolism, and lactate production [35]. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Vigorous exercise can contribute to capillary leakage, especially when left atrial pressure rises due to left ventricular (LV) systolic or diastolic insufficiency. LV diastolic dysfunction, which causes an increased pressure in the left atrium during exercise, often results in pulmonary edema and capillary hemorrhage. Studies suggest that the lungs can respond to exercise and immersion stress with pulmonary edema and pulmonary hemorrhage [36].

There are many controversial questions about the role of VEGF-A in the physiology and pathology of the lungs. Lung tissue contains the highest level of transcripts among the wide range of organs expressing VEGF-A. The lung is one of the main organs in which VEGF-A controls several important physiological functions [37]. Lung morphogenesis requires constant physical and molecular interactions between the mesenchymal stroma and epithelial elements. Airway epithelial cells are the predominant source of VEGF-A throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation during lung maturation, and normal vascular development. It is believed that VEGF-B, VEGF-C, VEGF-D, and PlGF also play a role in the physiological development of the lungs [38], but they are not extensively studied in this context or not so extensively as VEGF-A. There exists much research on these other growth factors. During exercise and airway activation, the lungs gradually receive a rich blood supply through the growth of endothelial cells and vascular cells in the pulmonary mesenchyme. This growth is accompanied by the expression of VEGF-A and its receptors, which play central morphogenetic functions in the lung tissue [39]. Pulmonary VEGF-A is synthesized by alveolar epithelial cells, bronchial epithelial cells, smooth muscle cells, and alveolar macrophages. This topographic compartmentalization allows VEGF-A to interact with components of the extracellular matrix, thereby creating concentration gradients that regulate the physiological functions of VEGF-A in the lungs [39]. Overexpression of pulmonary VEGF-A results in markedly dysmorphic lung structure. In contrast, neutralization of VEGF-A throughout fetal development by the extracellular domain Fc-VEGFR1 promotes a clearly simplified lung in neonatal mice [40,41]. Inhibition of VEGF-A leads to regression of tracheal capillaries and death of endothelial cells in the lungs of adult mice, while most vessels become resistant to VEGF-A cleavage after embryonic development [41]. It has recently been shown that this VEGF-A is an isoform of both VEGF-A xxx a and VEGF-A xxx b [42]. Similarly, VEGF-A receptors and coreceptors are also expressed by several types of cells in the normal lung on either side of the alveolar capillary membrane (ACM), including ATII cells. The classical processes associated with VEGF-A activity (permeability, angiogenesis, and mitogenesis) are extremely limited in the mature lung. Thus, although the exact role of VEGF-A in the lungs is not fully defined, it has been suggested that compartmentalization of VEGF-A in the alveolar space of intact lung tissue is essential to maintain normal lung structure and function.

In addition to its well-known functions as a trophic factor and growth factor, VEGF-A may play a new biological role in maintaining lung homeostasis. Cellular homeostasis of the lung tissue requires the rapid removal of apoptotic cells in order for their total number to remain constant. Effective removal of damaged cells reduces the risk of necrosis and inflammation, and by binding of apoptotic cells to the phosphatidylserine receptor, many immunosuppressive cytokines (TGF-β, PGE2, PGI2, and IL10) are released to suppress inflammation and reduce the risk of autoimmune diseases [43]. VEGF can promote efferocytosis, which, in turn, leads to further VEGF-A production and cell repair during lung tissue damage [44].

Chin-Kuo Lin et al. studied the expression patterns of inflammatory cytokines and growth factors after pulmonary hyperventilation (VILI) and determined the phenotypes of monocytes recruited to the lungs during recovery to elucidate how monocytes recruited to the lungs and pulmonary VEGF-A promote epithelial proliferation [45]. The increased expression of VEGF-A and TGF-β found by the authors in injured lungs underlines the role that VEGF-A and TGF-β play in lung recovery after VILI. Proteins belonging to the families of epidermal growth factor and fibroblast growth factor are involved in the restoration of damaged lung epithelium [46]. In addition to its well-known angiogenetic properties, VEGF-A acts as a powerful epithelial lung mitogen involved in repairing lung damage [47,48,49]. Studies have shown that the effects of VEGF-A vary depending on the damaged cells in the lung tissue and the recovery time [38,50,51]. VEGF-A receptor signaling is required for the maintenance of alveolar structures in normal rat lungs, as well as for the regulation of proliferation and apoptosis of damaged alveolar epithelial cells in an autocrine or paracrine manner [52]. Acute respiratory distress syndrome (ARDS) is the most severe form of lung disease. Medford et al. found that VEGF-A expression was significantly increased in late ARDS cases after day 7 compared with controls (without lung tissue damage) and early ARDS cases within 48 h [53]. Chin-Kuo Lin et al. [45] analyzed VEGF-A expression and the number of Ki67-positive cells in the alveolar epithelium of lung slices and found a strong positive correlation between VEGF-A expression and alveolar epithelial cell proliferation during VILI recovery. Their results demonstrated that VEGF-A can help repair alveoli in damaged lungs during healing [45]. Taken together, these findings suggest a dual role for VEGF-A in lung tissue repair: Increased serum VEGF-A concentration promotes progressive lung damage early in the disease, while increased VEGF-A expression in lung tissue promotes lung recovery during the late recovery phase. Thus, the revealed information about positive and negative effects of VEGF-A indicates that while considering the therapeutic effect of VEGF-A on lung tissue under intense physical activity the biology of VEGF-A in the lungs should be taken into account.

Skeletal muscle regeneration is largely controlled by FGFs, which are abundant in the regenerating muscle regions. Of greatest interest is the FGF6 isoform, as it is most specific for muscles and is strongly activated upon injury [63].

Yablonka-Reuveni et al. studied the role of FGF in recruiting skeletal muscle satellite cells. They demonstrated the high efficiency of the FGF2 isoform in stimulating the proliferation of satellite cells [64]. Doukas et al. investigated the activity of FGF isoforms in skeletal muscle recovery. In particular, plasmid and adenoviral vectors were immobilized in a collagen–gelatin mixture, which was then delivered to damaged muscle tissue. The results demonstrated an angiogenic response in muscles (microvascular development) in the early stages of injury. Subsequently, the authors discovered arteriogenesis or the development of higher-order vessels, which contained medial layers of smooth muscle cells, as well as increased muscle tube regeneration after delivery of FGF2 or FGF6 isoforms to damaged muscle tissue [65,66].

Richardson R.S. studied the expression of angiogenic growth factors in skeletal muscles in response to a single physical exercise (in particular, b-FGF and a-FGF in the gastrocnemius muscles) [67]. Animal models were injected with b-FGF and a-FGF intramuscularly into the right gastrocnemius muscle. Exercise significantly reduced vascularization in both the right and left calf muscles compared to control (without exercise), probably because of changes in muscle mass. Intramuscular injection of b-FGF significantly increased vascularization locally in the right muscle into which it was injected, while intramuscular injection of a-FGF did not lead to vascularization of the right muscle. With the simultaneous administration of angiogenic factors and physical activity, only b-FGF caused a significant local increase in vascular growth in the muscle under study. Neither b-FGF nor a-FGF elicited any angiogenic action on the left side. This can be explained by the one-sided effect of exercise.

Left ventricular hypertrophy is an adaptive response of the heart to exercise, but it is also a risk factor for cardiovascular mortality. Among the factors contributing to the transition from adaptive to pathological remodeling of the heart, an imbalance of the “angiogenic switch”, leading to the development of defects in cardiac angiogenesis and vascularization, plays a significant role [14]. Changes in hemodynamic and mechanical factors, as well as hypoxia, leading to a mismatch between the oxygen demand of the heart and its blood supply, stimulate the release of angiogenic growth factors from cardiomyocytes in order to cause a parallel growth of the feeding vasculature.

Major fibroblast growth factor (bFGF, also called FGF2) is also expressed in endothelial cells, including the heart, and has been shown to enhance the development of vascular collaterals in the myocardium in an animal model of coronary occlusion in dogs [68]. Rajanayagam et al. established the proangiogenic role of FGF2 in canine ischemic myocardium [69].

Alternatively, the role of FGF2 in myocardial vascularization during hypoxia caused by pressure overload is less well understood. For example, thyroxine, a potent stimulator of cardiac hypertrophy and vascularization, has been shown to enhance FGF2 expression and increase cardiac capillary endothelial cell proliferation and angiogenesis [70].

Santiago et al. investigated the differential effects of high and low molecular weight FGF2 isoforms on myocardial hypertrophy, fibrosis, and inflammation [71]. Echocardiographic measurements, gravimetry, and cross-sectional area of cardiomyocytes showed that the absence of FGF2 results in a statistically less degree of hypertrophy during pressure overload. The presented results demonstrate that FGF2 is the main stimulating component of the growth of myocardial hypertrophy. In addition, it was shown that hemodynamic stress, rather than FGF2 and myocardial hypertrophy, correlates with switching of the studied isoforms. Despite the fact that transcriptional and post-transcriptional control determine the ratios of myosin isoforms in cardiomyofibrils, the isoform switching that occurs during hemodynamic stress is the result of changes in transcriptional rather than posttranscriptional regulation.

Yajima et al. evaluated whether FGF2 and/or heparin, which induce angiogenesis, affect myocardial function in hypertensive conditions [72]. The study showed that intramyocardial injection of FGF2 (plus heparin) in rats with hypertensive myocardial hypertrophy was associated with significant improvements in systolic pumping function and ventricular dilatation, as well as an increase in myocardial capillary density.

Chen et al. investigated other isoforms of FGF, such as acidic fibroblast growth factor (sp-FGF1) or FGF1 [73]. It has been found that a secreted version of the FGF1 gene contributes to the functional improvement of disrupted endothelial progenitor cells and that autologous transplantation of modified sp-FGF1 in these cells may promote neovascularization in a porcine model of chronic myocardial ischemia.

To elucidate the pathophysiological role of FGF in cardiomyopathy, Tomita et al. evaluated myocardial biopsies from 24 patients (nine with hypertrophic cardiomyopathy, 12 with dilated cardiomyopathy, and three with hypertensive hypertrophy) and six controls. All samples were stained for FGF1 (also known as aFGF) and basic FGF (bFGF) by immunohistochemistry. FGF expression was significantly increased in cardiomyocytes obtained from the left ventricle of patients with cardiomyopathy. As it was revealed, FGF-1 can promote myocardial hypertrophy as a reparative response to myocardial damage in patients with idiopathic cardiomyopathy [74].

In recent years, a significant amount of knowledge has been accumulated on the regulation of the formation of new vessels in a hypertrophied heart [14]. It became clear that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also actively participate in the processes of cardiac remodeling, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. Moreover, in response to adequate signals, they can change their phenotype and transdifferentiate into extracellular cells that produce matrix. As myocardial vascularization plays a central role in the transition from adaptive cardiac hypertrophy to heart failure, endothelial cells and signaling mechanisms involved in the regulation or dysregulation of angiogenesis in the myocardium represent promising therapeutic targets for improving cardiac remodeling caused by pressure overload and preventing the transition to heart failure, which is important in sports practice.

FGFs constitute one of the most versatile and complex families of signaling in vertebrates, playing critical roles in a wide variety of biological processes, including a wide range of vascular functions. The multiple isoforms of FGFs generated by alternative splicing may play different roles in vascular development. FGFs are broad-spectrum mitogens that stimulate various cellular functions, including migration, proliferation, and differentiation [75]. The expression pattern of FGFs is highly variable, from almost ubiquitous (FGF1 and FGF2) to highly restricted, to certain cell subpopulations at certain stages of development (FGF3, FGF4, FGF8, FGF17, and FGF19). In pathological conditions such as inflammation, etc., FGF is secreted in large amounts by various types of cells, including monocytes, tissue macrophages, endothelial cells, stromal cells, and tumor cells [76].

Despite the recognition of FGF as a strong proangiogenic factor, the deciphering of its exact functions in the vascular system has not been adequately studied [77]. Mutations in the Fgfr1 or Fgfr2 genes in mouse embryos led to embryonic lethality at very early stages of development, which makes it impossible to further assess their contribution to vascular development [78]. By contrast, studies of angiogenic FGF isoforms such as FGF1 and FGF2 did not reveal abnormalities in embryonic vascular development, implying that there is significant redundancy in the system of these isoforms [79]. One of the difficulties in investigating the FGF system arises from its erratic action on various types of cells and tissues. However, using tissue-specific promoters, recent research has begun to uncover the role of FGFs in the “angiogenic switch” in the cardiovascular and cerebrovascular systems.

Analysis of FGF signaling in the vasculature of adult mice revealed a significant contribution of FGF to vascular development as well as maintaining vascular integrity. In adult mice, FGF is required for basal endothelial signaling and maintenance of vascular homeostasis. Inhibition of signaling through FGF leads to disassembly of endothelial junctions, progressing to severe disruption of vascular integrity [80]. In contrast to VEGF, which causes degradation of VE-cadherin-based compounds through activation of Src, FGF enhances the adhesion of the compounds by enhancing the binding of VE-cadherin to p120 catenin. The critical role of FGF signaling in neovascularization is also demonstrated in a more recent study that describes the cross-signaling mechanism between FGF and VEGF. The VEGFR2 gene expression levels are tightly controlled by endothelial FGF signaling, which is capable of activating VEGFR2 transcription through an Ets-dependent manner. Thus, FGF indirectly promotes neovascularization by regulating endothelial sensitivity to VEGF [81]. It has been repeatedly shown that although FGF-induced neovascularization is often impaired by VEGF inhibition in various angiogenic models, VEGF-induced vascular formation is not so strongly affected by depletion of FGF signaling [82]. Together, these studies support the hierarchical control of new vessel formation by which the FGF system promotes new vessel growth by controlling VEGF signaling.