Vascular Endothelial Growth Factor


Although lesser known and even less frequently considered as an important growth factor for the musculoskeletal system, Vascular Endothelial Growth Factor (VEGF) plays an essential role in muscle adaptations and bone health. Characteristically VEGF is known as a potent angiogenic growth factor and appears to be upregulated during hypoxic conditions. Below, we’ll discuss VEGF’s role in muscle and bone, how that relates to injury, and the potential benefits of upregulating an angiogenic hormone with our BFR prescription in rehab.

Muscle

Blood vessels in and around the muscle play a key role in a muscle’s ability to heal and adapt to stress. The density and availability of blood supply to the muscle helps to regulate the response of muscle stem cells (MuSC). MuSC, also known as satellite cells, are muscle specific progenitor cells capable of differentiating and incorporating into muscle tissue for healing following mechanical breakdown or to aid the growth response. Verma et al, found upwards of 80% of MuSC are in direct contact with capillaries while Christov et al found 63% of MuSC were surrounded by five or more capillaries, regardless of fiber type.(1,2) Interestingly, over a 24 week progressive resistance training program, muscle fibers with a lower capillary density showed no change in muscle mass, while muscle fibers with a higher capillary density demonstrated a significant increase in size.(3) The authors also found a significant increase in MuSC following 12 and 24 weeks of resistance training among individuals having a higher capillary density.(3)

To put this in a clinical perspective, early clinical data following an ACL injury shows a 30% reduction in vastus lateralis perfusion with a proportional reduction in MuSC.(4,5) Impressively, Zargi and colleagues showed five BFR training sessions in the eight days leading up to a ACLR resulted in a 52% increase in quadriceps blood flow and the ability to maintain an isometric contraction at 4 weeks postoperatively.(6) The control group, performing the same number of sessions without BFR demonstrated no change in blood flow to the quad contributing to a significant decrease in the ability to maintain an isometric contraction.(6) The increased vascular supply to the vastus lateralis, explained 71% of the variance in the ability to maintain a quadriceps isometric contraction at 4 weeks postoperatively.(6)

Bone

As mentioned previously, one of the major drivers contributing to the upregulation of VEGF is hypoxia. During fracture healing, the area within the hematoma is very hypoxic and induces a VEGF response from adjacent osteoblast and inflammatory cells that is approximately 15 fold greater than observed in circulating plasma.(7) As the fracture continues to heal, VEGF acts through its receptors in endothelial tissue, further increasing vascularity to enhance the delivery of nutrients required for osteogenesis. These nutrients include bone morphogenic protein (BMP) and mesenchymal stem cells, which ultimately differentiate into osteoblasts.(8)

In a recent presentation ahead of publication, Brad Lambert presented data from his randomized 12 week ACL post op trial conducted at Houston Methodist. Within the presentation, Lambert showed BFR rehab was able to prevent a loss of bone mineral density (BMD) in the distal femur and proximal tibia, while the group performing traditional rehab experienced significantly greater BMD loss at each location.

BFR and VEGF

In addition to the overall changes in muscle and bone referenced above, the direct relationship of BFR on VEGF has been looked at as well. Recently, Ferguson and colleagues showed VEGF levels increased 5.2 fold two hours following a single bout of BFR knee extensions and continued to increase to 6.8 fold at 4 hours post. Free flow knee extensions failed to increase VEGF levels.(9) More impressively, the upregulation of VEGF following an acute bout of low intensity BFR exercise is greater than the changes observed following a session of moderate to high intensity (60-80% 1RM) knee extensions.(10) These acute changes translated to a 14% increase in capillary density over a 6 week period in the BFR limb.(11) The increase in peripheral perfusion can also reduce the strain on the cardiovascular system as well. For instance, Kambič and colleagues found 8 weeks of BFR resistance exercise significantly lowered resting systolic blood pressure.(12)

The ability to upregulate VEGF can be crucial when the muscle or bone capillary network is disrupted, such as after an acute injury or prior to and following a surgery. Blood flow restriction exercise provides a way to target and manipulate VEGF within the constraints of low level exercise; hopefully resulting in better healing and restoration of function. When looking to upregulate VEGF and increase capillarity, the most important point to remember is to maintain a hypoxic environment. Previous research has shown a relative pressure between 60-80% LOP is needed to maintain an anaerobic environment.(9,13,14) It appears a similar set/rep scheme of BFR resistance exercise (30/15/15/failure) used to increase muscle mass and strength is able to provide a sufficient enough of a stimulus to maximize the response of VEGF. While a training frequency of 2-3 sessions/week for 4-6 weeks will likely maximize angiogenesis.

Check out a previous podcast we put out on hypoxia, HIF1A, and VEGF.

References

1. Verma M, Asakura Y, Murakonda BSR, et al. Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling. Cell Stem Cell. 2018;23(4):530-543.e9.

2. Christov C, Chrétien F, Abou-Khalil R, et al. Muscle satellite cells and endothelial cells: close neighbors and privileged partners. Mol Biol Cell. 2007;18(4):1397-1409.

3. Snijders T, Nederveen JP, Joanisse S, et al. Muscle fibre capillarization is a critical factor in muscle fibre hypertrophy during resistance exercise training in older men. J Cachexia Sarcopenia Muscle. 2017;8(2):267-276.

4. Grapar Zargi T, Drobnic M, Jkoder J, Strazar K, Kacin A. The effects of preconditioning with ischemic exercise on quadriceps femoris muscle atrophy following anterior cruciate ligament reconstruction: a quasi-randomized controlled trial. Eur J Phys Rehabil Med. 2016;52(3):310-320.

5. Noehren B, Andersen A, Hardy P, et al. Cellular and Morphological Alterations in the Vastus Lateralis Muscle as the Result of ACL Injury and Reconstruction. J Bone Joint Surg Am. 2016;98(18):1541-1547.

6. Žargi T, Drobnič M, Stražar K, Kacin A. Short–Term Preconditioning With Blood Flow Restricted Exercise Preserves Quadriceps Muscle Endurance in Patients After Anterior Cruciate Ligament Reconstruction. Front Physiol. 2018;9:1150.

7. Street J, Winter D, Wang JH, Wakai A, McGuinness A, Redmond HP. Is human fracture hematoma inherently angiogenic? Clin Orthop Relat Res. 2000;(378):224-237.

8. Mishima Y, Lotz M. Chemotaxis of human articular chondrocytes and mesenchymal stem cells. J Orthop Res. 2008;26(10):1407-1412.

9. Ferguson RA, Hunt JEA, Lewis MP, et al. The acute angiogenic signalling response to low-load resistance exercise with blood flow restriction. EJSS . 2018;18(3):397-406.

10. Gavin TP, Drew JL, Kubik CJ, Pofahl WE, Hickner RC. Acute resistance exercise increases skeletal muscle angiogenic growth factor expression. Acta Physiol . 2007;191(2):139-146.

11. Hunt JEA, Galea D, Tufft G, Bunce D, Ferguson RA. Time course of regional vascular adaptations to low load resistance training with blood flow restriction. J Appl Physiol. 2013;115(3):403-411.

12. Kambič T, Novaković M, Tomažin K, Strojnik V, Jug B. Blood Flow Restriction Resistance Exercise Improves Muscle Strength and Hemodynamics, but Not Vascular Function in Coronary Artery Disease Patients: A Pilot Randomized Controlled Trial. Front Physiol. 2019;10:656.

13. Hunt JEA, Stodart C, Ferguson RA. The influence of participant characteristics on the relationship between cuff pressure and level of blood flow restriction. Eur J Appl Physiol. 2016;116(7):1421-1432.

14. Ilett M, Rantalainen T, Keske M, May A, Warmington S. The Effects of Restriction Pressures on the Acute Responses to Blood Flow Restriction Exercise. Front Physiol. 2019;10:1018.