1. Vascular Adaptations to Exercise Presented by: Cody Shaffer May 5, 2005

2. Vascular Remodeling Outline  Vascular Anatomy  Arteriogenesis  Angiogenesis  Capillarization

3. Common Cardiovascular Adaptations to Exercise  Increased Heart Size (Hypertrophy)  Increased Stroke Volume  Increased Cardiac Output  Increased Blood Flow  Increased Vascular Density

4. Arterial Vascular Tree  Conduit Arteries (>1000 micro-meters)  Resistance Arteries (300-1000 micro-meters)  Arterioles (10-300 micro-meters)  Capillaries (<10 micro-meters)

5. Vascular Characteristics

6. Circulation Pathway

7. Vascular Function  Arteries function to rapidly transport the blood pumped from the heart. -Expand in Diameter  Capillaries function to exchange oxygen, fluid, nutrients, electrolytes, hormones, and other substances between the blood and interstitial fluid in various tissues of the body. -Increase in Numbers

8. Two Main Forms of Vascular Remodeling:  Arteriogenesis- Term applied to the enlargement of existing arterial vessels.  Angiogenesis- Formation of new capillaries from existing capillaries.

9. Steps of Remodeling Flow Chart:

10. Arteriogenesis  Occurs In Response To:  Elevated internal pressure within the vessel  Increased radial wall stress  Increased blood flow  Elevated stress on the endothelial surface

11. Arteriogenesis Cont.  Vessel wall mass will increase to manage the increased radial wall stress that occurs with high pressure or as the vessel diameter increases, according to the Laplace relationship.  Large increases in arterial blood pressure can also occur during intense modes of exercise.  Increases in flow velocity through a given arterial initiates extensive enlargement of the artery.  Increased flow velocity increases shear stress on vessel walls, which is considered to be the primary stimulus that prompts vessel enlargement.

12. Factors Implicated in Arteriogenesis  Arteriogensis depends on the presence of endothelium. Shear stress up-regulates numerous factors implicated in arteriogenesis. These Factors Include: Endothelial cell growth factors (VEGF) specifically VEGFR-2 Endothelial nitric oxide synthetase (eNOS)

13. Arteriogenic Factors  Increased shear stress experienced by the endothelium translates to a nitric oxide (NO)-dependent signal necessary for vessel enlargement involving remodeling of the extra cellular matrix.  NO is considered the most important mediator of flow-induced dilation.  Through flow induced release of NO vasodilation can be enhanced further and cellular growth response triggered either directly by endothelial factors or indirectly by stretch and altered mechanical stresses.

14. Arteriogenic Factors  Endothelial Cells react by activating endothelial NO synthetase (eNOS) and genes for cytokines such as monocyte chemoattractant protein-1 (MCP-1).  Aided by MCP-1 and adhesion molecules, circulating monocytes adhere to invade the vascular wall.  Invasion of monocytes in the region of the collaterals contributes to the vessel enlargement process via VEGF and fibroblast growth factor-2 (FGF-2).  After FGF-2 has bound to its receptors, endothelial and smooth muscle cell proliferation is stimulated.

15. Process of Arteriogenesis:

16. Adaptations to Specific Training  Huonker, M. et al. (1996)

17. Angiogenesis  Occurs In Response To:  Elevated internal pressure within the capillary  Increased radial wall stress  Increased blood flow  Elevated stress on the endothelial surface

18. ANGIOGENESIS

19. Two Forms of Angiogenesis:  Intusseception- Refers to the process by which a single capillary splits into two capillaries from within.  Sprouting- Refers to the process by which activated endothelial cells branch out from an existing capillary to form a cord-like structure.

20. Factors Implicated in Angiogenesis  There are many growth factors that are responsible increased capillarity:  VEGF is a potent mitogen of endothelial cells that has been implicated in the angiogenic response to exercise.  VEGF is required to maintain vascular integrity because in its absence there can be a rarefraction of vessels in the tissue.

21. Factors Implicated in Angiogenesis  VEGF acts in a proangiogenic manner that influences effectors of other important steps in the vascular remodeling process, including the following:  Cell signaling NO production.  Remodeling of the extra cellular matrix via up regulation of urokinase- and tissue-type plasminogen activator (uPA, tPA).  Up regulation of PA inhibitor (PAI-1) and uPA receptor (uPAR).  Up regulation of matrix metalloproteinase (MMP), which promotes chemotaxis to assist productive migration of cells in tube formation.

22. Other Roles of VEGF in Angiogenesis  VEGF is encoded by a single gene that is post-transcriptionally spliced into several different isoforms.  VEGF contains a signal sequence characteristic of protein designed for export from the cell.  VEGF is secreted by numerous tissue types, which establishes an extra cellular matrix (ECM) of VEGF that is available for action upon degradation of the ECM.  The VEGF gene contains an upstream regulatory sequence that increases VEGF and mRNA production when bound by hypoxia inducible factor (HIF1).

23. Angiopoietins and Angiogenesis  The angiopoitens (Ang1 and Ang 2) are recently discovered cytokins that effect vascular remodeling.  Ang1 promotes maturation and stabilization of vessels through binding to and activation of the endothelial cell- specific tyrosine receptor (Tie-2).  Ang2 augments angiogenesis by binding to but not activating Tie-2.

24. Angiopoitens Cont.  Ang2 to displaces Ang1 and destabilizes the vasculature and makes it more responsive to VEGF.  Ang1 and Ang2 are natural competitors to vascular remodeling.  Activity of Ang1 and Ang2 is dependent on the presence of VEGF and there interaction is critical in the angiogenic process.

25. Growth Factors Involved in Angiogenesis  Fibroblast growth factors (FGF) are a family of angiogenic growth factors that are mitogenic to all three of the cell types that comprise the vasculature.  FGF can aide in angiogeneis by up regulating VEGF and NO production.  FGF may also contribute to the continuation of angiogenesis as it is released from the storage sites upon the degradation of the EMC.  Activated endothelial cells can produce transforming growth factor-B (TGFb), which recruits pericytes to help complete the newly formed capillary.

26. OVERVIEW OF

27. Capillarization  The exercised induced adaptations that occur within the vascular tree increase the capillarity in tissues, organs, and specifically skeletal muscle.  Any increase in muscle capillarity is important in enhancing blood-tissue exchange properties.

28. Effects of Capillarization  A Greater Capillary Network: Increases surface are for diffusion. Shortens the average diffusion path-length within the muscle. Increases the time for diffusion exchange between the blood and tissue.

29. Capillarization  Refers to the increased capillarity within skeletal tissue.  Recent studies show that there is an even distribution of capillarity within all fiber types regardless of the mode of exercise.  Capillarization is determined by the number of capillaries in contact with each type of individual fiber (capillary-to-fiber ratio).

30. Capillarization Jensen et al. (2004)

31. Capillarization  A study conducted by Jensen et al., looked at the effect of intense training endothelial proliferation, capillary growth, and distribution of VEGF and FGFb.  Two intermittent knee extensor training protocols were conducted at 90% and 150% of leg VO 2 max.

32. Capillarization  Muscle biopsies were obtained throughout the training periods for immunohistochemical assessment of capillarization, cell proliferation, VEGF, and FGFb.  At 150% VO 2 max, micro dialysis samples were collected from the trained and untrained leg at rest and during exercise and added to endothelial cells to measure the proliferative effect.

33. Capillarization  After 4 weeks of training there was a higher capillary-to-fiber ratio and increased number of endothelial cell associated proliferating cells than before training.  Neither the location of proliferative endothelial cells nor capillarization was related to fiber type. The endothelial cell proliferative effect on of the muscle microdialysate increased from rest to exercise in both the trained and untrained leg.  VEGF and FGFb were localized in endothelial and skeletal muscle cells and training induced no changes in distribution.  The results demonstrate that intense intermittent exercise induces capillary growth and a transient proliferation of endothelial cells within 4 weeks, with a similar growth occurring around both fibers.

34. Capillarization Jensen et al. (2004) Changes in capillary-to-fiber ratio in (A), capillarity density (mm2) in (B), and proliferating cells (C) during the entire training protocol.

35. Summary  Exercise imparts a powerful stimulus for vascular remodeling and increased capillarity within working muscle, and an enlargement of arterial vessels increasing flow capacity to the muscle.  Vascular remodeling is a very intricate process that involves a complex coordination among angiogenic growth factors, receptors, and modulating influences including angiopoietins.  The vascular adaptations serve to enhance muscle performance by increasing capillarization by increasing the muscles oxygen exchange capacity and by increasing blood flow capacity.